Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells

Nature Reviews Cancer volume 24, pages 829–849 (2024)Cite this article

Subjects

Abstract

From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cancer-to-body connections.
Fig. 2: Cancer-derived pre-metastatic conditioning.
Fig. 3: Direct distant organ conditioning.
Fig. 4: Bone-marrow conditioning in the local and distal formation of pre-metastatic niches.
Fig. 5: Multi-organ and multi-system interactions between tumours and the host.

Similar content being viewed by others

References

  1. Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Kalluri, R. & McAndrews, K. M. The role of extracellular vesicles in cancer. Cell 186, 1610–1626 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Chen, G. et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382–386 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Gysler, S. M. & Drapkin, R. Tumor innervation: peripheral nerves take control of the tumor microenvironment. J. Clin. Investig. 131, e147276 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Francis, N. & Borniger, J. C. Cancer as a homeostatic challenge: the role of the hypothalamus. Trends Neurosci. 44, 903–914 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Borniger, J. C. et al. A role for hypocretin/orexin in metabolic and sleep abnormalities in a mouse model of non-metastatic breast cancer. Cell Metab. 28, 118–129.e5 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Hedrick, C. C. & Malanchi, I. Neutrophils in cancer: heterogeneous and multifaceted. Nat. Rev. Immunol. 22, 173–187 (2021).

    Article  PubMed  Google Scholar 

  8. Canonico, M. E. et al. Venous thromboembolism and cancer: a comprehensive review from pathophysiology to novel treatment. Biomolecules 12, 259 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Hisada, Y. & Mackman, N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood 130, 1499–1506 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

    Article  PubMed  CAS  Google Scholar 

  11. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005). Along with Hiratsuka et al. (ref. 10), this pioneering study demonstrates the ability of cancer cells to create a hospitable environment at distant sites prior to tumour-cell dissemination.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).

    Article  PubMed  CAS  Google Scholar 

  13. Patras, L., Shaashua, L., Matei, I. & Lyden, D. Immune determinants of the pre-metastatic niche. Cancer Cell 41, 546–572 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Boire, A. et al. Why do patients with cancer die? Nat. Rev. Cancer 24, 578–589 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Crist, S. B. & Ghajar, C. M. When a house is not a home: a survey of antimetastatic niches and potential mechanisms of disseminated tumor cell suppression. Annu. Rev. Pathol. Mech. Dis. 16, 409–432 (2021).

    Article  Google Scholar 

  16. de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

    Article  PubMed  Google Scholar 

  17. Cox, T. R. The matrix in cancer. Nat. Rev. Cancer 21, 217–238 (2021).

    Article  PubMed  CAS  Google Scholar 

  18. Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2011).

    Article  PubMed  Google Scholar 

  19. Oskarsson, T. et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 17, 867–874 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Patras, L., Paul, D. & Matei, I. R. Weaving the nest: extracellular matrix roles in pre-metastatic niche formation. Front. Oncol. 13, 1163786 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Deasy, S. K. & Erez, N. A glitch in the matrix: organ-specific matrisomes in metastatic niches. Trends Cell Biol. 32, 110–123 (2022).

    Article  PubMed  CAS  Google Scholar 

  22. Nielsen, S. R. et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat. Cell Biol. 18, 549–560 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Hiratsuka, S. et al. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc. Natl Acad. Sci. USA 108, 3725–3730 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. LIU, S. et al. Vascular endothelial growth factor plays a critical role in the formation of the pre-metastatic niche via prostaglandin E2. Oncol. Rep. 32, 2477–2484 (2014).

    Article  PubMed  CAS  Google Scholar 

  25. Hiratsuka, S. et al. Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. Nat. Commun. 4, 1853 (2013).

    Article  PubMed  Google Scholar 

  26. Seubert, B. et al. Tissue inhibitor of metalloproteinases (TIMP)‐1 creates a premetastatic niche in the liver through SDF‐1/CXCR4‐dependent neutrophil recruitment in mice. Hepatology 61, 238–248 (2015).

    Article  PubMed  CAS  Google Scholar 

  27. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485–498 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Qi, Y., Zhao, T., Li, R. & Han, M. Macrophage-secreted S100A4 supports breast cancer metastasis by remodeling the extracellular matrix in the premetastatic niche. BioMed. Res. Int. 2022, 9895504 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Martin, Y. et al. Mesenchymal cancer cell–stroma crosstalk promotes niche activation, epithelial reversion, and metastatic colonization. Cell Rep. 22, 2456–2469 (2015).

    Article  Google Scholar 

  30. Ji, Q. et al. Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nat. Commun. 11, 1211 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Moretti, L., Stalfort, J., Barker, T. H. & Abebayehu, D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J. Biol. Chem. 298, 101530 (2022).

    Article  PubMed  CAS  Google Scholar 

  32. Murgai, M. et al. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat. Med. 23, 1176–1190 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Gui, J. et al. Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs. Nat. Cancer 1, 603–619 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Tomita, T. et al. Extracellular mRNA transported to the nucleus exerts translation-independent function. Nat. Commun. 12, 3655 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Kong, J. et al. Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts. Mol. Cancer 18, 175 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Mazumdar, A. et al. Osteosarcoma-derived extracellular vesicles induce lung fibroblast reprogramming. Int. J. Mol. Sci. 21, 5451 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Wang, Y. et al. Tumor-derived Cav-1 promotes pre-metastatic niche formation and lung metastasis in breast cancer. Theranostics 13, 1684–1697 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Novo, D. et al. Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nat. Commun. 9, 5069 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhao, S. et al. Highly‐metastatic colorectal cancer cell released miR‐181a‐5p‐rich extracellular vesicles promote liver metastasis by activating hepatic stellate cells and remodelling the tumour microenvironment. J. Extracell. Vesicles 11, e12186 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Xie, Z. et al. Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment. Gut 71, 568–579 (2022).

    Article  PubMed  CAS  Google Scholar 

  41. Hsu, Y.-L. et al. Bone-marrow-derived cell-released extracellular vesicle miR-92a regulates hepatic pre-metastatic niche in lung cancer. Oncogene 39, 739–753 (2020).

    Article  PubMed  CAS  Google Scholar 

  42. Ju, C. & Tacke, F. Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies. Cell. Mol. Immunol. 13, 316–327 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Wu, S. et al. Matrix stiffness-upregulated LOXL2 promotes fibronectin production, MMP9 and CXCL12 expression and BMDCs recruitment to assist pre-metastatic niche formation. J. Exp. Clin. Cancer Res. 37, 99 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wu, S. et al. The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism. Eur. J. Cancer 147, 63–73 (2021).

    Article  PubMed  CAS  Google Scholar 

  46. Cohen, N. et al. Breast cancer-secreted factors promote lung metastasis by signaling systemically to induce a fibrotic premetastatic niche. Cancer Res. 83, 3354–3367 (2023).

    Article  PubMed  CAS  Google Scholar 

  47. Qi, M. et al. Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression. Nat. Commun. 13, 897 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Gong, Z. et al. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment. Immunity 55, 1483–1500.e9 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Grünwald, B. et al. Pancreatic premalignant lesions secrete tissue inhibitor of metalloproteinases-1, which activates hepatic stellate cells via CD63 signaling to create a premetastatic niche in the liver. Gastroenterology 151, 1011–1024.e7 (2016).

    Article  PubMed  Google Scholar 

  50. Zhang, H. et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat. Commun. 8, 15016 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Tian, F. et al. Exosome‐delivered miR‐221/222 exacerbates tumor liver metastasis by targeting SPINT1 in colorectal cancer. Cancer Sci. 112, 3744–3755 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Zhang, C. et al. Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell Death Dis. 13, 57 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Mo, Y. et al. Tumor-secreted exosomal miR-141 activates tumor–stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis. Mol. Cancer 22, 4 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Alvarez, M. V., Gutierrez, L. M., Correa, A., Lazarowski, A. & Bolontrade, M. F. Metastatic niches and the modulatory contribution of mesenchymal stem cells and its exosomes. Int. J. Mol. Sci. 20, 1946 (2019).

    Article  CAS  Google Scholar 

  55. Gong, Z. et al. Lipid-laden lung mesenchymal cells foster breast cancer metastasis via metabolic reprogramming of tumor cells and natural killer cells. Cell Metab. 34, 1960–1976.e9 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Li, P. et al. Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat. Immunol. 21, 1444–1455 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Zheng, Z. et al. Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3. Nat. Commun. 12, 6202 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Jiang, C. et al. Extracellular vesicles promotes liver metastasis of lung cancer by ALAHM increasing hepatocellular secretion of HGF. iScience 25, 103984 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Lee, J. W. et al. Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature 567, 249–252 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Liu, Y. et al. Tumor exosomal RNAs promote lung pre-metastatic niche formation by activating alveolar epithelial TLR3 to recruit neutrophils. Cancer Cell 30, 243–256 (2016). This key study identifies epithelial cells as active regulators of immune responses in the context of tumour-induced PMN formation.

    Article  PubMed  Google Scholar 

  61. Gu, P. et al. Breast tumor-derived exosomal microRNA-200b-3p promotes specific organ metastasis through regulating CCL2 expression in lung epithelial cells. Front. Cell Dev. Biol. 9, 657158 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wang, Z. et al. Tumor-polarized GPX3 + AT2 lung epithelial cells promote premetastatic niche formation. Proc. Natl Acad. Sci. USA 119, e2201899119 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Altea-Manzano, P. et al. A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling. Nat. Cancer 4, 344–364 (2023). This key study demonstrates how distal tumours shape the metabolic microenvironment of the PMN through increased local production of palmitate to support subsequent metastatic growth.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zhang, S., Lv, K., Liu, Z., Zhao, R. & Li, F. Fatty acid metabolism of immune cells: a new target of tumour immunotherapy. Cell Death Discov. 10, 39 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Pascual, G. et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541, 41–45 (2017).

    Article  PubMed  CAS  Google Scholar 

  66. Huang, Y. et al. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 69, 7529–7537 (2009).

    Article  PubMed  CAS  Google Scholar 

  67. Zhou, W. et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Fang, J. et al. Hepatoma cell‐secreted exosomal microRNA‐103 increases vascular permeability and promotes metastasis by targeting junction proteins. Hepatology 68, 1459–1475 (2018).

    Article  PubMed  CAS  Google Scholar 

  69. Zeng, Z. et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat. Commun. 9, 5395 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Duan, S., Nordmeier, S., Byrnes, A. E. & Buxton, I. L. O. Extracellular vesicle-mediated purinergic signaling contributes to host microenvironment plasticity and metastasis in triple negative breast cancer. Int. J. Mol. Sci. 22, 597 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Zeng, H. et al. Cancer-associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5-mediated angiogenesis and vascular permeability in breast cancer. Theranostics 12, 7351–7370 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Riera-Domingo, C. et al. Breast tumors interfere with endothelial TRAIL at the premetastatic niche to promote cancer cell seeding. Sci. Adv. 9, eadd5028 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Wieland, E. et al. Endothelial Notch1 activity facilitates metastasis. Cancer Cell 31, 355–367 (2017).

    Article  PubMed  CAS  Google Scholar 

  74. Mao, X. et al. Nidogen 1‐enriched extracellular vesicles facilitate extrahepatic metastasis of liver cancer by activating pulmonary fibroblasts to secrete tumor necrosis factor receptor 1. Adv. Sci. 7, 2002157 (2020).

    Article  CAS  Google Scholar 

  75. Hongu, T. et al. Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs. Nat. Cancer 3, 486–504 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Esposito, M. et al. Bone vascular niche E-selectin induces mesenchymal–epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat. Cell Biol. 21, 627–639 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Singhal, M. et al. Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis. Sci. Transl. Med. 13, eabe6805 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Rodrigues, G. et al. Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat. Cell Biol. 21, 1403–1412 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Wu, D. et al. TGF-β1-mediated exosomal lnc-MMP2-2 increases blood–brain barrier permeability via the miRNA-1207-5p/EPB41L5 axis to promote non-small-cell lung cancer brain metastasis. Cell Death Dis. 12, 721 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Doron, H., Pukrop, T. & Erez, N. A blazing landscape: neuroinflammation shapes brain metastasis. Cancer Res. 79, 423–436 (2018).

    Article  Google Scholar 

  81. Gan, D.-X. et al. Lung cancer cells-controlled Dkk-1 production in brain metastatic cascade drive microglia to acquire a pro-tumorigenic phenotype. Front. Cell Dev. Biol. 8, 591405 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Stacker, S. A. et al. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat. Rev. Cancer 14, 159–172 (2014).

    Article  PubMed  CAS  Google Scholar 

  83. Reticker-Flynn, N. E. et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell 185, 1924–1942.e23 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Gillot, L. et al. Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization. Cell Mol. Life Sci. 79, 295 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Leary, N. et al. Melanoma‐derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes. J. Extracell. Vesicles 11, e12197 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. García-Silva, S. et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat. Cancer 2, 1387–1405 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Olmeda, D. et al. Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine. Nature 546, 676–680 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Shao, Y. et al. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 39, 1368–1379 (2018).

    Article  PubMed  CAS  Google Scholar 

  89. Jiang, K. et al. Exosomal ANGPTL1 attenuates colorectal cancer liver metastasis by regulating Kupffer cell secretion pattern and impeding MMP9 induced vascular leakiness. J. Exp. Clin. Cancer Res. 40, 21 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Sun, H. et al. Hypoxia‐inducible exosomes facilitate liver‐tropic premetastatic niche in colorectal cancer. Hepatology 74, 2633–2651 (2021).

    Article  PubMed  CAS  Google Scholar 

  91. Li, B. et al. miR-151a-3p-rich small extracellular vesicles derived from gastric cancer accelerate liver metastasis via initiating a hepatic stemness-enhancing niche. Oncogene 40, 6180–6194 (2021).

    Article  PubMed  CAS  Google Scholar 

  92. Li, W., Yang, Y., Yang, L., Chang, N. & Li, L. Monocyte-derived Kupffer cells dominate in the Kupffer cell pool during liver injury. Cell Rep. 42, 113164 (2023).

    Article  PubMed  CAS  Google Scholar 

  93. Güç, E. & Pollard, J. W. Redefining macrophage and neutrophil biology in the metastatic cascade. Immunity 54, 885–902 (2021).

    Article  PubMed  Google Scholar 

  94. Aegerter, H., Lambrecht, B. N. & Jakubzick, C. V. Biology of lung macrophages in health and disease. Immunity 55, 1564–1580 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395.e6 (2018).

    Article  PubMed  CAS  Google Scholar 

  96. Guldner, I. H. et al. CNS-native myeloid cells drive immune suppression in the brain metastatic niche through Cxcl10. Cell 183, 1234–1248.e25 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Klemm, F. et al. Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis. Nat. Cancer 2, 1086–1101 (2021).

    Article  PubMed  CAS  Google Scholar 

  98. Hanna, R. N. et al. Patrolling monocytes control tumor metastasis to the lung. Science 350, 985–990 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Chen, T. & Zhao, L. Patrolling monocytes inhibit osteosarcoma metastasis to the lung. Aging 12, 23004–23016 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  100. Plebanek, M. P. et al. Pre-metastatic cancer exosomes induce immune surveillance by patrolling monocytes at the metastatic niche. Nat. Commun. 8, 1319 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Han, Y. et al. Citrullinated fibrinogen–SAAs complex causes vascular metastagenesis. Nat. Commun. 14, 4960 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Gil-Bernabé, A. M. et al. Recruitment of monocytes/macrophages by tissue factor-mediated coagulation is essential for metastatic cell survival and premetastatic niche establishment in mice. Blood 119, 3164–3175 (2012).

    Article  PubMed  Google Scholar 

  103. Zhao, S. et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J. Hematol. Oncol. 13, 156 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Qiu, S. et al. Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis. J. Exp. Clin. Cancer Res. 41, 296 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Morrissey, S. M. et al. Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab. 33, 2040–2058.e10 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Ruf, B., Greten, T. F. & Korangy, F. Innate lymphoid cells and innate-like T cells in cancer—at the crossroads of innate and adaptive immunity. Nat. Rev. Cancer 23, 351–371 (2023).

    Article  PubMed  CAS  Google Scholar 

  107. Long, A. et al. Type 2 innate lymphoid cells impede IL-33-mediated tumor suppression. J. Immunol. 201, 3456–3464 (2018).

    Article  PubMed  CAS  Google Scholar 

  108. Schuijs, M. J. et al. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung. Nat. Immunol. 21, 998–1009 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Chan, I. S. & Ewald, A. J. The changing role of natural killer cells in cancer metastasis. J. Clin. Investig. 132, e143762 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Lazarova, M. & Steinle, A. Impairment of NKG2D-mediated tumor immunity by TGF-β. Front. Immunol. 10, 2689 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Slattery, K. et al. TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer. J. Immunother. Cancer 9, e002044 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 (2017).

    Article  PubMed  CAS  Google Scholar 

  113. Braun, A., Anders, H.-J., Gudermann, T. & Mammadova-Bach, E. Platelet–cancer interplay: molecular mechanisms and new therapeutic avenues. Front. Oncol. 11, 665534 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Leal, A. C. et al. Tumor-derived exosomes induce the formation of neutrophil extracellular traps: implications for the establishment of cancer-associated thrombosis. Sci. Rep. 7, 6438 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Lucotti, S. et al. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2. J. Clin. Investig. 129, 1845–1862 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kerr, B. A. et al. Platelet TSP-1 controls prostate cancer-induced osteoclast differentiation and bone marrow-derived cell mobilization through TGFβ-1. Am. J. Clin. Exp. Urol. 9, 18–31 (2020).

    Google Scholar 

  117. Kerr, B. A., McCabe, N. P., Feng, W. & Byzova, T. V. Platelets govern pre-metastatic tumor communication to bone. Oncogene 32, 4319–4324 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Wculek, S. K. & Malanchi, I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature 528, 413–417 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Quail, D. F. et al. Neutrophil phenotypes and functions in cancer: a consensus statement. J. Exp. Med. 219, e20220011 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Giese, M. A., Hind, L. E. & Huttenlocher, A. Neutrophil plasticity in the tumor microenvironment. Blood 133, 2159–2167 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Nolan, E. et al. Radiation exposure elicits a neutrophil-driven response in healthy lung tissue that enhances metastatic colonization. Nat. Cancer 3, 173–187 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  122. Ballesteros, I. et al. Co-option of neutrophil fates by tissue environments. Cell 183, 1282–1297.e18 (2020).

    Article  PubMed  CAS  Google Scholar 

  123. Alshetaiwi, H. et al. Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics. Sci. Immunol. 5, eaay6017 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Veglia, F. et al. Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice. J. Exp. Med. 218, e20201803 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Zhu, Y. P. et al. Identification of an early unipotent neutrophil progenitor with pro-tumoral activity in mouse and human bone marrow. Cell Rep. 24, 2329–2341.e8 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Evrard, M. et al. Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions. Immunity 48, 364–379.e8 (2018).

    Article  PubMed  CAS  Google Scholar 

  127. Dinh, H. Q. et al. Coexpression of CD71 and CD117 identifies an early unipotent neutrophil progenitor population in human bone marrow. Immunity 53, 319–334.e6 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Bao, Y. et al. Extramedullary hematopoiesis secondary to malignant solid tumors: a case report and literature review. Cancer Manag. Res. 10, 1461–1470 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Casbon, A.-J. et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc. Natl Acad. Sci. USA 112, E566–E575 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Coffelt, S. B. et al. IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis. Nature 522, 345–348 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Gerber-Ferder, Y. et al. Breast cancer remotely imposes a myeloid bias on haematopoietic stem cells by reprogramming the bone marrow niche. Nat. Cell Biol. 25, 1736–1745 (2023).

    Article  PubMed  CAS  Google Scholar 

  132. LaMarche, N. M. et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 625, 166–174 (2024). This key study provides important mechanistic insight into myelopoiesis in cancer, including the identification of an IL-4-dependent axis within the bone marrow that directs GMP fate towards the production of monocytes and macrophages imprinted with immunosuppressive phenotypes, thus offering novel routes to potential therapies.

    Article  PubMed  CAS  Google Scholar 

  133. Engblom, C. et al. Osteoblasts remotely supply lung tumors with cancer-promoting SiglecF high neutrophils. Science 358, eaal5081 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Wellenstein, M. D. et al. Loss of p53 triggers Wnt-dependent systemic inflammation to drive breast cancer metastasis. Nature 572, 538–542 (2019). This important study demonstrates how tumour-intrinsic heterogeneity, notably cancer cell p53 status, has important implications for the generation of pro-metastatic systemic inflammatory responses.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Hao, X. et al. Osteoprogenitor–GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal. Cell Stem Cell 30, 648–664.e8 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Ma, R.-Y. et al. Monocyte-derived macrophages promote breast cancer bone metastasis outgrowth. J. Exp. Med. 217, e20191820 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Sanmartin, M. C. et al. Bone marrow/bone pre-metastatic niche for breast cancer cells colonization: the role of mesenchymal stromal cells. Crit. Rev. Oncol. Hematol. 164, 103416 (2021).

    Article  PubMed  CAS  Google Scholar 

  138. Yue, Z. et al. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. J. Clin. Investig. 132, e144579 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Yip, R. K. H. et al. Mammary tumour cells remodel the bone marrow vascular microenvironment to support metastasis. Nat. Commun. 12, 6920 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Chen, H.-M., Chen, F.-P., Yang, K.-C. & Yuan, S.-S. Association of bone metastasis with early-stage breast cancer in women with and without precancer osteoporosis according to osteoporosis therapy status. JAMA Netw. Open 2, e190429 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Szczerba, B. M. et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 566, 553–557 (2019).

    Article  PubMed  CAS  Google Scholar 

  142. Chen, M. B. et al. Inflamed neutrophils sequestered at entrapped tumor cells via chemotactic confinement promote tumor cell extravasation. Proc. Natl Acad. Sci. USA 115, 7022–7027 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Patel, S. et al. Unique pattern of neutrophil migration and function during tumor progression. Nat. Immunol. 19, 1236–1247 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Veglia, F. et al. Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature 569, 73–78 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Rice, C. M. et al. Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression. Nat. Commun. 9, 5099 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Li, P. et al. Dual roles of neutrophils in metastatic colonization are governed by the host NK cell status. Nat. Commun. 11, 4387 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Yang, L. et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature 583, 133–138 (2020). This study offers key mechanistic insights into how cancer cells detect and actively respond to NETs within the PMN, enhancing their migration, adhesion and metastatic colonization.

    Article  PubMed  CAS  Google Scholar 

  148. Lee, W. et al. Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. J. Exp. Med. 216, 176–194 (2018).

    Article  PubMed  Google Scholar 

  149. Li, C. et al. FGF19‐induced inflammatory CAF promoted neutrophil extracellular trap formation in the liver metastasis of colorectal cancer. Adv. Sci. 10, 2302613 (2023).

    Article  CAS  Google Scholar 

  150. Zeng, Z. et al. HAO1-mediated oxalate metabolism promotes lung pre-metastatic niche formation by inducing neutrophil extracellular traps. Oncogene 41, 3719–3731 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Su, X. et al. Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis. J. Extracell. Vesicles 12, 12341 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Zhang, Q. et al. ETV4 mediated tumor‐associated neutrophil infiltration facilitates lymphangiogenesis and lymphatic metastasis of bladder cancer. Adv. Sci. 10, 2205613 (2023).

    Article  CAS  Google Scholar 

  153. Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Castaño, Z. et al. IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization. Nat. Cell Biol. 20, 1084–1097 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Stehr, A. M. et al. Neutrophil extracellular traps drive epithelial–mesenchymal transition of human colon cancer. J. Pathol. 256, 455–467 (2022).

    Article  PubMed  CAS  Google Scholar 

  156. Wang, Y. et al. Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer. Int. J. Biol. Sci. 19, 1352–1368 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Thuya, W. L. et al. FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites. Theranostics 13, 621–638 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Wang, J., Tan, S., Gianotti, L. & Wu, G. Evaluation and management of body composition changes in cancer patients. Nutrition 114, 112132 (2023).

    Article  PubMed  Google Scholar 

  159. Ferrer, M. et al. Cachexia: a systemic consequence of progressive, unresolved disease. Cell 186, 1824–1845 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 27, 152–164 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Hu, S., Hu, Y. & Yan, W. Extracellular vesicle-mediated interorgan communication in metabolic diseases. Trends Endocrinol. Metab. 34, 571–582 (2023).

    Article  PubMed  CAS  Google Scholar 

  162. Yan, W. et al. Cancer-cell-secreted miR-122 suppresses O-GlcNAcylation to promote skeletal muscle proteolysis. Nat. Cell Biol. 24, 793–804 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Cao, M. et al. Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth. Nat. Cell Biol. 24, 954–967 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Wang, G. et al. Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature 618, 374–382 (2023). This landmark study uncovers how tumour-derived EVs disrupt broader host physiology by inducing systemic metabolic alterations through EV-mediated perturbations of hepatocyte function.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Hu, Y. et al. Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia. Nat. Commun. 14, 5179 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Xie, H. et al. An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia. Proc. Natl Acad. Sci. USA 119, e2112840119 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Fan, Y. & Pedersen, O. Gut microbiota in human metabolic health and disease. Nat. Rev. Microbiol. 19, 55–71 (2021).

    Article  PubMed  CAS  Google Scholar 

  168. Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med. 375, 2369–2379 (2016).

    Article  Google Scholar 

  169. Yonekura, S. et al. Cancer induces a stress ileopathy depending on B-adrenergic receptors and promoting dysbiosis that contributes to carcinogenesis. Cancer Discov. 12, candisc.0999.2021 (2021).

    Google Scholar 

  170. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    Article  PubMed  CAS  Google Scholar 

  172. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  PubMed  CAS  Google Scholar 

  174. Hawley, J. A. Microbiota and muscle highway—two-way traffic. Nat. Rev. Endocrinol. 16, 71–72 (2020).

    Article  PubMed  Google Scholar 

  175. Park, E. M. et al. Targeting the gut and tumor microbiota in cancer. Nat. Med. 28, 690–703 (2022).

    Article  PubMed  CAS  Google Scholar 

  176. Qu, M. Molecular crosstalk between circadian clock and cancer and therapeutic implications. Front. Nutr. 10, 1143001 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Masri, S. et al. Lung adenocarcinoma distally rewires hepatic circadian homeostasis. Cell 165, 896–909 (2016). This study identifies the circadian rhythm as a biological process affected by cancer cells (specifically lung cancer cells) within the primary tumour and the consequent disruption of liver metabolism.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Diamantopoulou, Z. et al. The metastatic spread of breast cancer accelerates during sleep. Nature 607, 156–162 (2022).

    Article  PubMed  CAS  Google Scholar 

  179. He, X.-Y. et al. Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment. Cancer Cell 42, 474–486.e12 (2024). This landmark study reveals the impact of chronic stress, an inevitable aspect of a cancer diagnosis, on the tissue microenvironment, highlighting how stress-induced glucocorticoids induce pro-metastatic neutrophil phenotypes, notably NETosis, to create a pro-metastatic tissue microenvironment.

    Article  PubMed  CAS  Google Scholar 

  180. Perego, M. et al. Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils. Sci. Transl. Med. 12, eabb5817 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. McDowell, S. A. C. et al. Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration. Nat. Cancer 2, 545–562 (2021).

    Article  PubMed  CAS  Google Scholar 

  182. Tyagi, A. et al. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung. Nat. Commun. 12, 474 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Zhao, J. et al. Interorgan communication with the liver: novel mechanisms and therapeutic targets. Front. Immunol. 14, 1314123 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Li, D. et al. Hepatocytes derived increased SAA1 promotes intrahepatic platelet aggregation and aggravates liver inflammation in NAFLD. Biochem. Biophys. Res. Commun. 555, 54–60 (2021).

    Article  PubMed  CAS  Google Scholar 

  185. Severe, N. et al. Stress-induced changes in bone marrow stromal cell populations revealed through single-cell protein expression mapping. Cell Stem Cell 25, 570–583.e7 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  186. Campbell, J. P. et al. Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice. PLoS Biol. 10, e1001363 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  187. Zheng, Y. et al. Chronic psychological stress promotes breast cancer pre-metastatic niche formation by mobilizing splenic MDSCs via TAM/CXCL1 signaling. J. Exp. Clin. Cancer Res. 42, 129 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Fane, M. E. et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 606, 396–405 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  189. Turrell, F. K. et al. Age-associated microenvironmental changes highlight the role of PDGF-C in ER+ breast cancer metastatic relapse. Nat. Cancer 4, 468–484 (2023). This important study uncovers a key role for ageing-associated changes to the tissue microenvironment in regulating the metastatic dormancy of breast cancer.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021).

    Article  PubMed  CAS  Google Scholar 

  191. Barkaway, A. et al. Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage. Immunity 54, 1494–1510.e7 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Nishi, K. et al. Age-associated myeloid biased hematopoiesis depends on relative decrease of short-term hematopoietic stem cell. Blood 134, 2481 (2019).

    Article  Google Scholar 

  193. López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L. & Kroemer, G. Meta-hallmarks of aging and cancer. Cell Metab. 35, 12–35 (2023).

    Article  PubMed  Google Scholar 

  194. Quail, D. F. et al. Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat. Cell Biol. 19, 974–987 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Ladanyi, A. et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 37, 2285–2301 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Qiu, M. et al. Modulation of intestinal microbiota by glycyrrhizic acid prevents high-fat diet-enhanced pre-metastatic niche formation and metastasis. Mucosal Immunol. 12, 945–957 (2019).

    Article  PubMed  CAS  Google Scholar 

  197. Cheng, P. et al. Capsaicin shapes gut microbiota and pre-metastatic niche to facilitate cancer metastasis to liver. Pharmacol. Res. 188, 106643 (2023).

    Article  PubMed  CAS  Google Scholar 

  198. Collins, N. et al. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 178, 1088–1101.e15 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Collins, N. & Belkaid, Y. Control of immunity via nutritional interventions. Immunity 55, 210–223 (2022).

    Article  PubMed  CAS  Google Scholar 

  200. Sheinboim, D. et al. An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination. Cancer Res. 82, 4164–4178 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Gomes-Santos, I. L. et al. Exercise training improves tumor control by increasing CD8+ T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade. Cancer Immunol. Res. 9, 765–778 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Darkwah, S. et al. Potential roles of muscle-derived extracellular vesicles in remodeling cellular microenvironment: proposed implications of the exercise-induced myokine, irisin. Front. Cell Dev. Biol. 9, 634853 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Seki, T. et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature 608, 421–428 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Xiao, T. et al. Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications. Nat. Rev. Cancer 24, 338–355 (2024).

    Article  PubMed  CAS  Google Scholar 

  205. Dunford, A. et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat. Genet. 49, 10–16 (2017).

    Article  PubMed  CAS  Google Scholar 

  206. Zhong, X. & Zimmers, T. A. Sex differences in cancer cachexia. Curr. Osteopor. Rep. 18, 646–654 (2020).

    Article  Google Scholar 

  207. Permuth, J. B. et al. Racial and ethnic disparities in a state‐wide registry of patients with pancreatic cancer and an exploratory investigation of cancer cachexia as a contributor to observed inequities. Cancer Med. 8, 3314–3324 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Keklikoglou, I. et al. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat. Cell Biol. 21, 190–202 (2019).

    Article  PubMed  CAS  Google Scholar 

  209. Mousset, A. et al. Neutrophil extracellular traps formed during chemotherapy confer treatment resistance via TGF-β activation. Cancer Cell 41, 757–775.e10 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  210. Monteran, L. et al. Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer. Nat. Commun. 13, 5797 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  211. Wu, C. et al. Reactive myelopoiesis and FX-expressing macrophages triggered by chemotherapy promote cancer lung metastasis. JCI Insight 8, e167499 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Sagiv, J. Y. et al. Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer. Cell Rep. 10, 562–573 (2015).

    Article  PubMed  Google Scholar 

  213. Gershkovitz, M. et al. TRPM2 mediates neutrophil killing of disseminated tumor cells. Cancer Res. 78, 2680–2690 (2018).

    Article  PubMed  CAS  Google Scholar 

  214. Piranlioglu, R. et al. Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model. Nat. Commun. 10, 1430 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015). This landmark study uncovers how organ specificity of metastases can be generated by tumour-intrinsic mechanisms involving release of exosomes with organ-homing properties determined by the matched integrin expression and ECM make-up of target tissues.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  216. Lee, Y. J., Shin, K. J. & Chae, Y. C. Regulation of cargo selection in exosome biogenesis and its biomedical applications in cancer. Exp. Mol. Med. 56, 877–889 (2024).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Contreras-Zárate, M. J. et al. Estradiol induces BDNF/TrkB signaling in triple-negative breast cancer to promote brain metastases. Oncogene 38, 4685–4699 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  218. Heitz, F. et al. Cerebral metastases in metastatic breast cancer: disease-specific risk factors and survival. Ann. Oncol. 22, 1571–1581 (2011).

    Article  PubMed  CAS  Google Scholar 

  219. Lu, Z. et al. Epigenetic therapy inhibits metastases by disrupting premetastatic niches. Nature 579, 284–290 (2020). This important study demonstrates how epigenetic therapies can be leveraged to reprogramme pro-metastatic cancer-primed myeloid cells and prevent PMN formation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Kaczanowska, S. et al. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell 184, 2033–2052.e21 (2021). This groundbreaking study demonstrates how the inflammatory characteristics of the PMN can be harnessed to develop an engineered myeloid-cell-based therapy that reprogrammes the tissue microenvironment through targeted cytokine production and effectively reverses PMN formation. It offers proof-of-concept for using cell-based therapies to deliver therapeutic cargo into the PMN to prevent metastasis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. He, B. et al. Remodeling of metastatic vasculature reduces lung colonization and sensitizes overt metastases to immunotherapy. Cell Rep. 30, 714–724.e5 (2020).

    Article  PubMed  CAS  Google Scholar 

  222. Ortiz, A. et al. An interferon-driven oxysterol-based defense against tumor-derived extracellular vesicles. Cancer Cell 35, 33–45.e6 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Barron, T. I., Connolly, R. M., Sharp, L., Bennett, K. & Visvanathan, K. Beta blockers and breast cancer mortality: a population- based study. J. Clin. Oncol. 29, 2635–2644 (2011).

    Article  PubMed  CAS  Google Scholar 

  224. Spera, G. et al. Beta blockers and improved progression-free survival in patients with advanced HER2 negative breast cancer: a retrospective analysis of the ROSE/TRIO-012 study. Ann. Oncol. 28, 1836–1841 (2017).

    Article  PubMed  CAS  Google Scholar 

  225. Piccolo, N. D. et al. Tumor-on-chip modeling of organ-specific cancer and metastasis. Adv. Drug Deliv. Rev. 175, 113798 (2021).

    Article  PubMed  Google Scholar 

  226. Kim, J. et al. Three-dimensional human liver-chip emulating premetastatic niche formation by breast cancer-derived extracellular vesicles. ACS Nano 14, 14971–14988 (2020).

    Article  PubMed  CAS  Google Scholar 

  227. Aleman, J. & Skardal, A. A multi‐site metastasis‐on‐a‐chip microphysiological system for assessing metastatic preference of cancer cells. Biotechnol. Bioeng. 116, 936–944 (2019).

    Article  PubMed  CAS  Google Scholar 

  228. Colombo, M. V. et al. Engineering the early bone metastatic niche through human vascularized immuno bone minitissues. Biofabrication 13, 035036 (2021).

    Article  CAS  Google Scholar 

  229. Picollet-D’hahan, N., Zuchowska, A., Lemeunier, I. & Gac, S. L. Multiorgan-on-a-chip: a systemic approach to model and decipher inter-organ communication. Trends Biotechnol. 39, 788–810 (2021).

    Article  PubMed  Google Scholar 

  230. Wang, J. et al. A synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs. Nat. Commun. 14, 4790 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  231. Aguado, B. A. et al. Biomaterial scaffolds as pre‐metastatic niche mimics systemically alter the primary tumor and tumor microenvironment. Adv. Healthc. Mater. 7, e1700903 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Aguado, B. A. et al. Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche. Acta Biomater. 33, 13–24 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  233. Xia, C. et al. Sponge-like nano-system suppresses tumor recurrence and metastasis by restraining myeloid-derived suppressor cells-mediated immunosuppression and formation of pre-metastatic niche. Acta Biomater. 158, 708–724 (2023).

    Article  PubMed  CAS  Google Scholar 

  234. Xia, J. et al. Versatile ginsenoside Rg3 liposomes inhibit tumor metastasis by capturing circulating tumor cells and destroying metastatic niches. Sci. Adv. 8, eabj1262 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  235. Silvers, C. R., Messing, E. M., Miyamoto, H. & Lee, Y.-F. Tenascin-C expression in the lymph node pre-metastatic niche in muscle-invasive bladder cancer. Br. J. Cancer 125, 1399–1407 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Ramessur, A. et al. Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes. Breast Cancer Res. 25, 125 (2023).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Liu, Z. et al. Liquid biopsy in pre-metastatic niche: from molecular mechanism to clinical application. Front. Immunol. 13, 958360 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  238. Penders, J. et al. Single particle automated Raman trapping analysis of breast cancer cell-derived extracellular vesicles as cancer biomarkers. ACS Nano 15, 18192–18205 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  239. Li, R. et al. Computed tomography reveals microenvironment changes in premetastatic lung. Eur. Radiol. 31, 4340–4349 (2021).

    Article  PubMed  Google Scholar 

  240. Liang, M. et al. Whole-liver enhanced CT radiomics analysis to predict metachronous liver metastases after rectal cancer surgery. Cancer Imaging 22, 50 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Qi, Y. et al. Radiomics analysis of lung CT image for the early detection of metastases in patients with breast cancer: preliminary findings from a retrospective cohort study. Eur. Radiol. 30, 4545–4556 (2020).

    Article  PubMed  Google Scholar 

  242. Granot, Z. et al. Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell 20, 300–314 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge funding support from a European Research Council grant (ERC CoG-H2020725492) and the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001112), the UK Medical Research Council (FC001112), and the Wellcome Trust (FC001112).

Author information

Author notes

  1. These authors contributed equally: Nicolas Rabas, Rute M. M. Ferreira.

Authors and Affiliations

  1. Tumour–Host Interaction Laboratory, The Francis Crick Institute, London, UK

    Nicolas Rabas, Rute M. M. Ferreira, Stefania Di Blasio & Ilaria Malanchi

Authors
  1. Nicolas Rabas
    View author publications

    Search author on:PubMed Google Scholar

  2. Rute M. M. Ferreira
    View author publications

    Search author on:PubMed Google Scholar

  3. Stefania Di Blasio
    View author publications

    Search author on:PubMed Google Scholar

  4. Ilaria Malanchi
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to researched data for the article. All authors contributed substantially to discussion of the content. N.R., R.M.M.F. and I.M. wrote the article, reviewed and edited the manuscript. S.D.B. wrote and reviewed parts of the manuscript before submission.

Corresponding author

Correspondence to Ilaria Malanchi.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Ana Correia, Sachie Hiratsuka, who co-reviewed with Norihiro Ashihara, and Xiang Zhang, who co-reviewed with Fengshuo Liu, for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Adipoblasts

Specialized cells of the adipose tissue derived from mesenchymal stem cells that function as precursors of adipocytes.

Bone resorption

Process by which osteoclasts dissolve the minerals in bone and break down the matrix.

Cachexia

Complex multiorgan syndrome causing wasting of the body.

Chronic unpredictable mild stress

(CUMS). Animal model of depression and stress characterized by exposure to a combination of mild and randomly administered sources of stress such as food and water deprivation, tilting of the cage, physical restraint and forced swimming. The purpose of this model is to mimic the stress in daily human life.

Citrullination

Process by which the amino acid arginine is converted into citrulline by post-translational modifications catalysed by peptidyl arginine deaminases, also referred to as deamination.

Decellularized matrices

Extracellular matrix from biological origins that have been processed to remove their cellular components to obtain a scaffold of the site-specific extracellular protein composition.

Degranulation

Action carried out by specialized cells that is characterized by the release of intracellular granules.

Granulopoiesis

Haematological process whereby granulocytes — namely neutrophils, eosinophils and basophils — are produced. This process is enhanced under certain inflammatory contexts and termed emergency granulopoiesis.

Hyperglycaemia

High levels of blood glucose in the absence of external glucose sources (such as food) during periods of fasting.

Lipolysis

Metabolic process to mobilize energy via the hydrolysis of triglycerides into glycerol and free fatty acids.

Long non-coding RNA

RNA sequences usually of about 200 nucleotides that are not translated into proteins.

Lymphangiogenesis

Physiological process for the formation and growth of new lymphatic vessels from pre-existing ones.

Matrisome

Chemical and biophysical composition of the extracellular matrix.

Microbiome

The microbiota naturally living in the human body at a given location or habitat. The term usually used in the context of the intestine is ‘gut microbiome’.

Microglia

Resident macrophages of the nervous system.

Myelopoiesis

Biological process for the formation of all myeloid cells (such as monocytes and granulocytes) from undifferentiated bone marrow progenitor cells.

Myofibroblasts

Specialized type of activated fibroblast, usually characterized by the expression of α-smooth-muscle actin and exhibiting a smooth-muscle (spindle) morphology.

Neurovascular unit

(NVU). Anatomical structure that provides integrity and regulates the blood–brain barrier. Composed of cerebral vascular cells and surrounding neurons, glia and extracellular matrix.

Neutrophil extracellular trap

(NET). An extracellular network of decondensed DNA and proteases from neutrophils, usually formed in the context of pathogens. The neutrophil specific process of NET release is known as NETosis.

Omentum

A multi-layered specialized tissue of the peritoneum.

Osteoblasts

Specialized cells originating from the monocyte lineage in the bone marrow whose function is to synthesize bone tissue.

Osteoclast

A specialized cell originating from the monocyte lineage in the bone marrow whose function is to break down bone tissue.

Osteoclastogenesis

The biological processes involved in bone degradation including osteoclast differentiation and bone resorption.

Pancreatic β-cells

Neuroendocrine pancreatic cells responsible for insulin production.

Purinergic signalling

Extracellular signalling mediated by purine nucleotides, such as ATP.

Thromboembolism

Vascular obstruction due to the formation of a blood clot.

Thrombosis

Formation of a blood clot.

White adipose tissue

(WAT). The most abundant type of adipose tissue involved in energy storage, endocrine communication and insulin sensitivity.

White adipose tissue browning

Metabolic adaptation to increased thermogenic demand characterized by the development of brown adipose tissue or the conversion of white adipocytes into beige adipocytes.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rabas, N., Ferreira, R.M.M., Di Blasio, S. et al. Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells. Nat Rev Cancer 24, 829–849 (2024). https://doi.org/10.1038/s41568-024-00752-0

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41568-024-00752-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer