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How the bone microenvironment shapes the pre-metastatic niche and metastasis

Nature Cancer volume 5, pages 1800–1814 (2024)Cite this article

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Abstract

The bone is a frequent metastatic site, with changes in the mineralized bone and the bone marrow milieu that can also prime other sites for metastasis by educating progenitor cells to support metastatic spread. Stromal and immune populations cooperatively maintain the organizationally complex bone niches and are dysregulated in the presence of a distant primary tumor and metastatic disease. Interrogating the bone niches that facilitate metastatic spread using innovative technologies holds the potential to aid in preventing metastasis in and mediated by the bone. Here, we review recent advances in bone niche biology and its adaptations in the context of cancer.

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Fig. 1: Bone vascular niches and cellular communities.
Fig. 2: Dysregulation of stromal and immune cell microenvironments throughout bone metastasis.
Fig. 3: Methods for capturing spatially and temporally resolved stromal–immune interactions in bone metastasis.

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References

  1. Macedo, F. et al. Bone metastases: an overview. Oncol. Rev. 11, 321 (2017).

    PubMed  PubMed Central  Google Scholar 

  2. Zhang, W. et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 184, 2471–2486 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huang, Y., Wang, H., Yue, X. & Li, X. Bone serves as a transfer station for secondary dissemination of breast cancer. Bone Res. 11, 21 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  5. Giles, A. J. et al. Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Res. 76, 1335–1347 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Kaplan, R. N., Psaila, B. & Lyden, D. Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Rev. 25, 521–529 (2006).

    Article  PubMed  Google Scholar 

  7. Giles, A. J. et al. The functional interplay between systemic cancer and the hematopoietic stem cell niche. Pharmacol. Ther. 168, 53–60 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zacharia, B., Joy, J., Subramaniam, D. & Pai, P. K. Factors affecting life expectancy after bone metastasis in adults — results of a 5-year prospective study. Indian J. Surg. Oncol. 12, 759–769 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  9. LaMarche, N. M. et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 625, 166–174 (2024).

    Article  CAS  PubMed  Google Scholar 

  10. Akkiraju, H. & Nohe, A. Current challenges in bone biology. Adv. Tech. Biol. Med. 3, 132 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Safi, S. et al. Bone marrow expands the repertoire of functional T cells targeting tumor-associated antigens in patients with resectable non-small-cell lung cancer. Oncoimmunology 8, e1671762 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chen, J. Z. & Alt, F. W. Gene rearrangement and B-cell development. Curr. Opin. Immunol. 5, 194–200 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Geerman, S., Hickson, S., Brasser, G., Pascutti, M. F. & Nolte, M. A. Quantitative and qualitative analysis of bone marrow CD8+ T cells from different bones uncovers a major contribution of the bone marrow in the vertebrae. Front. Immunol. 6, 660 (2015).

    PubMed  Google Scholar 

  14. Fornetti, J., Welm, A. L. & Stewart, S. A. Understanding the bone in cancer metastasis. J. Bone Miner. Res. 33, 2099–2113 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Lazic, D. et al. Landscape of bone marrow metastasis in human neuroblastoma unraveled by transcriptomics and deep multiplex imaging. Cancers 13, 4311 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lim, W. et al. Real-time in vivo imaging of metastatic bone tumors with a targeted near-infrared fluorophore. Oncotarget 8, 65770–65777 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lecomte, J. et al. Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor. Neoplasia 14, 943–951 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pittenger, M. F. et al. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen. Med. 4, 22 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Pinho, S. & Frenette, P. S. Haematopoietic stem cell activity and interactions with the niche. Nat. Rev. Mol. Cell Biol. 20, 303–320 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sivaraj, K. K. & Adams, R. H. Blood vessel formation and function in bone. Development 143, 2706–2715 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Kusumbe, A. P., Ramasamy, S. K. & Adams, R. H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507, 323–328 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kusumbe, A. P., Ramasamy, S. K., Starsichova, A. & Adams, R. H. Sample preparation for high-resolution 3D confocal imaging of mouse skeletal tissue. Nat. Protoc. 10, 1904–1914 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Stucker, S., Chen, J., Watt, F. E. & Kusumbe, A. P. Bone angiogenesis and vascular niche remodeling in stress, aging, and diseases. Front. Cell Dev. Biol. 8, 602269 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Peng, Y., Wu, S., Li, Y. & Crane, J. L. Type H blood vessels in bone modeling and remodeling. Theranostics 10, 426–436 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen, M. et al. Skeleton–vasculature chain reaction: a novel insight into the mystery of homeostasis. Bone Res. 9, 21 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Biswas, L. et al. Lymphatic vessels in bone support regeneration after injury. Cell 186, 382–397 (2023).

    Article  CAS  PubMed  Google Scholar 

  27. Marrella, A. et al. Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration. Mater. Today 21, 362–376 (2018).

    Article  CAS  Google Scholar 

  28. Qin, Q. et al. Neurovascular coupling in bone regeneration. Exp. Mol. Med. 54, 1844–1849 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brazill, J. M., Beeve, A. T., Craft, C. S., Ivanusic, J. J. & Scheller, E. L. Nerves in bone: evolving concepts in pain and anabolism. J. Bone Miner. Res. 34, 1393–1406 (2019).

    Article  PubMed  Google Scholar 

  30. Wolock, S. L. et al. Mapping distinct bone marrow niche populations and their differentiation paths. Cell Rep. 28, 302–311 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tikhonova, A. N. et al. The bone marrow microenvironment at single-cell resolution. Nature 569, 222–228 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Baccin, C. et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat. Cell Biol. 22, 38–48 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Gomariz, A. et al. Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy. Nat. Commun. 9, 2532 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zhao, E. et al. Bone marrow and the control of immunity. Cell. Mol. Immunol. 9, 11–19 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Leitao, L. et al. Bone marrow cell response after injury and during early stage of regeneration is independent of the tissue-of-injury in 2 injury models. FASEB J. 33, 857–872 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Comazzetto, S., Shen, B. & Morrison, S. J. Niches that regulate stem cells and hematopoiesis in adult bone marrow. Dev. Cell 56, 1848–1860 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shiozawa, Y. et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 121, 1298–1312 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Carsetti, R. The development of B cells in the bone marrow is controlled by the balance between cell-autonomous mechanisms and signals from the microenvironment. J. Exp. Med. 191, 5–8 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zehentmeier, S. & Pereira, J. P. Cell circuits and niches controlling B cell development. Immunol. Rev. 289, 142–157 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zanna, M. Y. et al. Review of dendritic cells, their role in clinical immunology, and distribution in various animal species. Int. J. Mol. Sci. 22, 8044 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Soltan, M., Rohrer, M. D. & Prasad, H. S. Monocytes: super cells for bone regeneration. Implant Dent. 21, 13–20 (2012).

    Article  PubMed  Google Scholar 

  42. Kaur, S. et al. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches. Semin. Cell Dev. Biol. 61, 12–21 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Kraus, R. F. & Gruber, M. A. Neutrophils—from bone marrow to first-line defense of the innate immune system. Front. Immunol. 12, 767175 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bonomo, A. et al. A T cell view of the bone marrow. Front. Immunol. 7, 184 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Guder, C., Gravius, S., Burger, C., Wirtz, D. C. & Schildberg, F. A. Osteoimmunology: a current update of the interplay between bone and the immune system. Front. Immunol. 11, 58 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sun, Y. et al. Macrophage–osteoclast associations: origin, polarization, and subgroups. Front. Immunol. 12, 778078 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sender, R. et al. The total mass, number, and distribution of immune cells in the human body. Proc. Natl Acad. Sci. USA 120, e2308511120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fichtel, P. et al. Mesenchymal stromal cell-derived extracellular vesicles modulate hematopoietic stem and progenitor cell viability and the expression of cell cycle regulators in an age-dependent manner. Front. Bioeng. Biotechnol. 10, 892661 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Krebsbach, P. H., Kuznetsov, S. A., Bianco, P. & Robey, P. G. Bone marrow stromal cells: characterization and clinical application. Crit. Rev. Oral Biol. Med. 10, 165–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Jiang, W. & Xu, J. Immune modulation by mesenchymal stem cells. Cell Prolif. 53, e12712 (2020).

    Article  PubMed  Google Scholar 

  51. Crippa, S. & Bernardo, M. E. Mesenchymal stromal cells: role in the BM niche and in the support of hematopoietic stem cell transplantation. Hemasphere 2, e151 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wu, J. Y., Scadden, D. T. & Kronenberg, H. M. Role of the osteoblast lineage in the bone marrow hematopoietic niches. J. Bone Miner. Res. 24, 759–764 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mangialardi, G., Cordaro, A. & Madeddu, P. The bone marrow pericyte: an orchestrator of vascular niche. Regen. Med. 11, 883–895 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sato, S. et al. Bone marrow adipocytes induce cancer-associated fibroblasts and immune evasion, enhancing invasion and drug resistance. Cancer Sci. 114, 2674–2688 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yamazaki, S. & Nakauchi, H. Bone marrow Schwann cells induce hematopoietic stem cell hibernation. Int. J. Hematol. 99, 695–698 (2014).

    Article  CAS  PubMed  Google Scholar 

  56. Wei, Q. & Frenette, P. S. Niches for hematopoietic stem cells and their progeny. Immunity 48, 632–648 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Bandyopadhyay, S. et al. Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging. Cell 187, 3120–3140 (2024).

    Article  CAS  PubMed  Google Scholar 

  58. Gao, X. et al. Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor. Nat. Cell Biol. 25, 1746–1757 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kaczanowska, S. et al. Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis. Cell 184, 2033–2052 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. O’Donnell, R. K. et al. VEGF-A/VEGFR inhibition restores hematopoietic homeostasis in the bone marrow and attenuates tumor growth. Cancer Res. 76, 517–524 (2016).

    Article  PubMed  Google Scholar 

  62. Li, X. et al. Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFκB–TLR signaling pathway. J. Hematol. Oncol. 9, 42 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Meng, D. et al. Effects of VEGFR1+ hematopoietic progenitor cells on pre-metastatic niche formation and in vivo metastasis of breast cancer cells. J. Cancer Res. Clin. Oncol. 145, 411–427 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. Kusmartsev, S. et al. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J. Immunol. 181, 346–353 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Anastasiadou, D. P., Quesnel, A., Duran, C. L., Filippou, P. S. & Karagiannis, G. S. An emerging paradigm of CXCL12 involvement in the metastatic cascade. Cytokine Growth Factor Rev. 75, 12–30 (2024).

    Article  CAS  PubMed  Google Scholar 

  66. Wang, Z. et al. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis. J. Pathol. 239, 484–495 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Wang, Y. G., Ding, Y. X., Guo, N. Z. & Wang, S. J. MDSCs: key criminals of tumor pre-metastatic niche formation. Front. Immunol. 10, 172 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu, Y. & Cao, X. Characteristics and significance of the pre-metastatic niche. Cancer Cell 30, 668–681 (2016).

    Article  CAS  PubMed  Google Scholar 

  69. 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  CAS  PubMed  PubMed Central  Google Scholar 

  70. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  71. 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  CAS  PubMed  Google Scholar 

  72. 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  74. Peinado, H., Lavotshkin, S. & Lyden, D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin. Cancer Biol. 21, 139–146 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Li, X. Q., Zhang, R., Lu, H., Yue, X. M. & Huang, Y. F. Extracellular vesicle-packaged CDH11 and ITGA5 induce the premetastatic niche for bone colonization of breast cancer cells. Cancer Res. 82, 1560–1574 (2022).

    Article  CAS  PubMed  Google Scholar 

  76. Maroni, P., Gomarasca, M. & Lombardi, G. Long non-coding RNAs in bone metastasis: progresses and perspectives as potential diagnostic and prognostic biomarkers. Front. Endocrinol. 14, 1156494 (2023).

    Article  Google Scholar 

  77. Cheng, J., Zhang, K., Qu, C., Peng, J. & Yang, L. Non-coding RNAs derived from extracellular vesicles promote pre-metastatic niche formation and tumor distant metastasis. Cancers 15, 2158 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lu, X. & Kang, Y. Chemokine (C–C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J. Biol. Chem. 284, 29087–29096 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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  CAS  PubMed  Google Scholar 

  80. Jing, B. et al. IL6/STAT3 signaling orchestrates premetastatic niche formation and immunosuppressive traits in lung. Cancer Res. 80, 784–797 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Cai, R. et al. Primary breast tumor induced extracellular matrix remodeling in premetastatic lungs. Sci. Rep. 13, 18566 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sun, Y. X. et al. Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J. Cell. Biochem. 89, 462–473 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Kai, F., Drain, A. P. & Weaver, V. M. The extracellular matrix modulates the metastatic journey. Dev. Cell 49, 332–346 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Si, J., Wang, C., Zhang, D., Wang, B. & Zhou, Y. Osteopontin in bone metabolism and bone diseases. Med. Sci. Monit. 26, e919159 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shen, X. & Falzon, M. Parathyroid hormone-related protein upregulates integrin expression via an intracrine pathway in PC-3 prostate cancer cells. Regul. Pept. 113, 17–29 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Guise, T. A. et al. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J. Clin. Invest. 98, 1544–1549 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Isali, I. et al. Growth factors involve in cellular proliferation, differentiation and migration during prostate cancer metastasis. Int. J. Cell Biol. Physiol. 2, 1–13 (2019).

    PubMed  PubMed Central  Google Scholar 

  89. Dougherty, K. M. et al. Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. Cancer Res. 59, 6015–6022 (1999).

    CAS  PubMed  Google Scholar 

  90. Swami, S. et al. Parathyroid hormone 1 receptor signaling mediates breast cancer metastasis to bone in mice. JCI Insight 8, e157390 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Paiva, A. E. et al. Pericytes in the premetastatic niche. Cancer Res. 78, 2779–2786 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Shankman, L. S. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat. Med. 21, 628–637 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Singh, A. et al. Angiocrine signals regulate quiescence and therapy resistance in bone metastasis. JCI Insight 4, e125679 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang, Z. M. et al. Metastasis-associated fibroblasts: an emerging target for metastatic cancer. Biomark. Res. 9, 47 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Deborde, S. & Wong, R. J. The role of Schwann cells in cancer. Adv. Biol. 6, e2200089 (2022).

    Article  Google Scholar 

  97. Sun, C. C. et al. Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion. Sci. Adv. 9, eadd6995 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kitamura, T. et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J. Exp. Med. 212, 1043–1059 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lin, Y. X., Xu, J. X. & Lan, H. Y. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J. Hematol. Oncol. 12, 76 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Monteiro, A. C. et al. T cells induce pre-metastatic osteolytic disease and help bone metastases establishment in a mouse model of metastatic breast cancer. PLoS ONE 8, e68171 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang, R., Peng, S. & Zhu, G. The role of secreted osteoclastogenic factor of activated T cells in bone remodeling. Jpn. Dent. Sci. Rev. 58, 227–232 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Clements, M. E. & Johnson, R. W. Breast cancer dormancy in bone. Curr. Osteoporos. Rep. 17, 353–361 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Ghajar, C. M. et al. The perivascular niche regulates breast tumour dormancy. Nat. Cell Biol. 15, 807–817 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kunisaki, Y. et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502, 637–643 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Nobre, A. R. et al. Bone marrow NG2+/nestin+ mesenchymal stem cells drive DTC dormancy via TGFβ2. Nat. Cancer 2, 327–339 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sandiford, O. A. et al. Mesenchymal stem cell-secreted extracellular vesicles instruct stepwise dedifferentiation of breast cancer cells into dormancy at the bone marrow perivascular region. Cancer Res. 81, 1567–1582 (2021).

    Article  CAS  PubMed  Google Scholar 

  108. Zhao, L. et al. The relationship between mesenchymal stem cells and tumor dormancy. Front. Cell Dev. Biol. 9, 731393 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Gasson, J. C. Molecular physiology of granulocyte–macrophage colony-stimulating factor. Blood 77, 1131–1145 (1991).

    Article  CAS  PubMed  Google Scholar 

  110. Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging Notch signaling in bone cells. Cancer Cell 19, 192–205 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bidwell, B. N. et al. Silencing of Irf7 pathways in breast cancer cells promotes bone metastasis through immune escape. Nat. Med. 18, 1224–1231 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. 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 

  113. Mayhew, V., Omokehinde, T. & Johnson, R. W. Tumor dormancy in bone. Cancer Rep. 3, e1156 (2020).

    Article  Google Scholar 

  114. Monteran, L. et al. Bone metastasis is associated with acquisition of mesenchymal phenotype and immune suppression in a model of spontaneous breast cancer metastasis. Sci. Rep. 10, 13838 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yao, K. et al. Multidimensional analysis to elucidate the possible mechanism of bone metastasis in breast cancer. BMC Cancer 23, 1213 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Orimo, A. et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Wang, M., Xia, F., Wei, Y. & Wei, X. Molecular mechanisms and clinical management of cancer bone metastasis. Bone Res. 8, 30 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kozlow, W. & Guise, T. A. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J. Mammary Gland Biol. Neoplasia 10, 169–180 (2005).

    Article  PubMed  Google Scholar 

  119. Ibrahim, T. et al. Pathogenesis of osteoblastic bone metastases from prostate cancer. Cancer 116, 1406–1418 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Coleman, R. E. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin. Cancer Res. 12, 6243s–6249s (2006).

    Article  PubMed  Google Scholar 

  121. Zhang, L., Zhang, J., Li, Z., Wu, Y. & Tong, Z. Comparison of the clinicopathological characteristics and prognosis between Chinese patients with breast cancer with bone-only and non-bone-only metastasis. Oncol. Lett. 20, 92 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hartkopf, A. D. et al. Prognostic relevance of disseminated tumour cells from the bone marrow of early stage breast cancer patients — results from a large single-centre analysis. Eur. J. Cancer 50, 2550–2559 (2014).

    Article  PubMed  Google Scholar 

  123. Braun, S., Auer, D. & Marth, C. The prognostic impact of bone marrow micrometastases in women with breast cancer. Cancer Invest. 27, 598–603 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Chin, H. & Kim, J. Bone metastasis: concise overview. Fed. Pract. 32, 24–30 (2015).

    PubMed  PubMed Central  Google Scholar 

  125. Liu, C. et al. Immune checkpoint inhibitor therapy for bone metastases: specific microenvironment and current situation. J. Immunol. Res. 2021, 8970173 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Kfoury, Y. et al. Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment. Cancer Cell 39, 1464–1478 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Reinstein, Z. Z. et al. Overcoming immunosuppression in bone metastases. Crit. Rev. Oncol. Hematol. 117, 114–127 (2017).

    Article  PubMed  Google Scholar 

  128. Edwards, S. C., Hoevenaar, W. H. M. & Coffelt, S. B. Emerging immunotherapies for metastasis. Br. J. Cancer 124, 37–48 (2021).

    Article  PubMed  Google Scholar 

  129. Jiao, S. et al. Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell 179, 1177–1190 (2019).

    Article  Google Scholar 

  130. Le Rochais, M., Hemon, P., Pers, J. O. & Uguen, A. Application of high-throughput imaging mass cytometry Hyperion in cancer research. Front. Immunol. 13, 859414 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Cheng, S., Nethi, S. K., Rathi, S., Layek, B. & Prabha, S. Engineered mesenchymal stem cells for targeting solid tumors: therapeutic potential beyond regenerative therapy. J. Pharmacol. Exp. Ther. 370, 231–241 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Richardson, D. S. & Lichtman, J. W. Clarifying tissue clearing. Cell 162, 246–257 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Schrijver, W. A. et al. Influence of decalcification procedures on immunohistochemistry and molecular pathology in breast cancer. Mod. Pathol. 29, 1460–1470 (2016).

    Article  CAS  PubMed  Google Scholar 

  134. Sadozai, H. et al. Distinct stromal and immune features collectively contribute to long-term survival in pancreatic cancer. Front. Immunol. 12, 643529 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Sowder, M. E. & Johnson, R. W. Enrichment and detection of bone disseminated tumor cells in models of low tumor burden. Sci. Rep. 8, 14299 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Black, S. et al. CODEX multiplexed tissue imaging with DNA-conjugated antibodies. Nat. Protoc. 16, 3802–3835 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hipps, D. et al. Detecting respiratory chain defects in osteoblasts from osteoarthritic patients using imaging mass cytometry. Bone 158, 116371 (2022).

    Article  PubMed  Google Scholar 

  138. Qiao, H. & Tang, T. Engineering 3D approaches to model the dynamic microenvironments of cancer bone metastasis. Bone Res. 6, 3 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Salamanna, F., Contartese, D., Maglio, M. & Fini, M. A systematic review on in vitro 3D bone metastases models: a new horizon to recapitulate the native clinical scenario? Oncotarget 7, 44803–44820 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Coutu, D. L., Kokkaliaris, K. D., Kunz, L. & Schroeder, T. Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules. Nat. Biotechnol. 35, 1202–1210 (2017).

    Article  CAS  PubMed  Google Scholar 

  141. Kokkaliaris, K. D. et al. Adult blood stem cell localization reflects the abundance of reported bone marrow niche cell types and their combinations. Blood 136, 2296–2307 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Agarwal, P. et al. Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells. Cell Stem Cell 26, 123 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Gruneboom, A. et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat. Metab. 1, 236–250 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Mai, H. et al. Whole-body cellular mapping in mouse using standard IgG antibodies. Nat. Biotechnol. 42, 617–627 (2024).

    Article  CAS  PubMed  Google Scholar 

  145. Renier, N. et al. iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging. Cell 159, 896–910 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Chung, K. et al. Structural and molecular interrogation of intact biological systems. Nature 497, 332–337 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Li, W., Germain, R. N. & Gerner, M. Y. High-dimensional cell-level analysis of tissues with Ce3D multiplex volume imaging. Nat. Protoc. 14, 1708–1733 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Molino, G., Montalbano, G., Pontremoli, C., Fiorilli, S. & Vitale-Brovarone, C. Imaging techniques for the assessment of the bone osteoporosis-induced variations with particular focus on micro-CT potential. Appl. Sci. 10, 8939 (2020).

    Article  CAS  Google Scholar 

  149. Jovic, D. et al. Single-cell RNA sequencing technologies and applications: a brief overview. Clin. Transl. Med. 12, e694 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Ombrato, L. et al. Metastatic-niche labelling reveals parenchymal cells with stem features. Nature 572, 603–608 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Marx, V. Method of the year: spatially resolved transcriptomics. Nat. Methods 18, 9–14 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Du, J. et al. Advances in spatial transcriptomics and related data analysis strategies. J. Transl. Med. 21, 330 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Godet, I. et al. Fate-mapping post-hypoxic tumor cells reveals a ROS-resistant phenotype that promotes metastasis. Nat. Commun. 10, 4862 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Anderson, M., Moshnikova, A., Engelman, D. M., Reshetnyak, Y. K. & Andreev, O. A. Probe for the measurement of cell surface pH in vivo and ex vivo. Proc. Natl Acad. Sci. USA 113, 8177–8181 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hasegawa, T., Kikuta, J. & Ishii, M. Imaging the bone–immune cell interaction in bone destruction. Front. Immunol. 10, 596 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Dondossola, E. et al. Intravital microscopy of osteolytic progression and therapy response of cancer lesions in the bone. Sci. Transl. Med. 10, eaao5726 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Christodoulou, C. et al. Live-animal imaging of native haematopoietic stem and progenitor cells. Nature 578, 278–283 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Junt, T. et al. Dynamic visualization of thrombopoiesis within bone marrow. Science 317, 1767–1770 (2007).

    Article  CAS  PubMed  Google Scholar 

  160. Upadhaya, S. et al. Intravital imaging reveals motility of adult hematopoietic stem cells in the bone marrow niche. Cell Stem Cell 27, 336–345 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Bixel, M. G. et al. Flow dynamics and HSPC homing in bone marrow microvessels. Cell Rep. 18, 1804–1816 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hawkins, E. D. et al. T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments. Nature 538, 518–522 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Tang, R. et al. A versatile system to record cell–cell interactions. eLife 9, e61080 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Graham, N. & Qian, B. Z. Mesenchymal stromal cells: emerging roles in bone metastasis. Int. J. Mol. Sci. 19, 1121 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Ara, T. & Declerck, Y. A. Interleukin-6 in bone metastasis and cancer progression. Eur. J. Cancer 46, 1223–1231 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Mukaida, N., Zhang, D. & Sasaki, S. I. Emergence of cancer-associated fibroblasts as an indispensable cellular player in bone metastasis process. Cancers 12, 2896 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Delprat, V., Huart, C., Feron, O., Soncin, F. & Michiels, C. The impact of macrophages on endothelial cells is potentiated by cycling hypoxia: enhanced tumor inflammation and metastasis. Front. Oncol. 12, 961753 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Paiva, A. E. et al. Endothelial cells as precursors for osteoblasts in the metastatic prostate cancer bone. Neoplasia 19, 928–931 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Raymaekers, K., Stegen, S., van Gastel, N. & Carmeliet, G. The vasculature: a vessel for bone metastasis. BoneKEy Rep. 4, 742 (2015).

    PubMed  PubMed Central  Google Scholar 

  170. Luo, G., He, Y. & Yu, X. Bone marrow adipocyte: an intimate partner with tumor cells in bone metastasis. Front. Endocrinol. 9, 339 (2018).

    Article  Google Scholar 

  171. Dai, R., Liu, M., Xiang, X., Xi, Z. & Xu, H. Osteoblasts and osteoclasts: an important switch of tumour cell dormancy during bone metastasis. J. Exp. Clin. Cancer Res. 41, 316 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ottewell, P. D. The role of osteoblasts in bone metastasis. J. Bone Oncol. 5, 124–127 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Lawson, M. A. et al. Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche. Nat. Commun. 6, 8983 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Riquelme, M. A., Cardenas, E. R. & Jiang, J. X. Osteocytes and bone metastasis. Front. Endocrinol. 11, 567844 (2020).

    Article  Google Scholar 

  175. Anloague, A. & Delgado-Calle, J. Osteocytes: new kids on the block for cancer in bone therapy. Cancers 15, 2645 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Navarro, R., Compte, M., Alvarez-Vallina, L. & Sanz, L. Immune regulation by pericytes: modulating innate and adaptive immunity. Front. Immunol. 7, 480 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Er, E. E. et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat. Cell Biol. 20, 966–978 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Sun, L., Chen, S. & Chen, M. Schwann cells in the tumor microenvironment: need more attention. J. Oncol. 2022, 1058667 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Deborde, S. et al. Schwann cells induce cancer cell dispersion and invasion. J. Clin. Invest. 126, 1538–1554 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Zhang, S. H. et al. Immunomodulation by Schwann cells in disease. Cancer Immunol. Immunother. 69, 245–253 (2020).

    Article  PubMed  Google Scholar 

  181. Elefteriou, F. Role of sympathetic nerves in the establishment of metastatic breast cancer cells in bone. J. Bone Oncol. 5, 132–134 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Yoneda, T., Hiasa, M., Okui, T. & Hata, K. Sensory nerves: a driver of the vicious cycle in bone metastasis? J. Bone Oncol. 30, 100387 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  183. Shurin, M. R., Shurin, G. V., Zlotnikov, S. B. & Bunimovich, Y. L. The neuroimmune axis in the tumor microenvironment. J. Immunol. 204, 280–285 (2020).

    Article  CAS  PubMed  Google Scholar 

  184. Leblanc, R. et al. Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone. Blood 124, 3141–3150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Anvari, S., Osei, E. & Maftoon, N. Interactions of platelets with circulating tumor cells contribute to cancer metastasis. Sci. Rep. 11, 15477 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Schwartz, M., Zhang, Y. & Rosenblatt, J. D. B cell regulation of the anti-tumor response and role in carcinogenesis. J. Immunother. Cancer 4, 40 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Xiang, L. & Gilkes, D. M. The contribution of the immune system in bone metastasis pathogenesis. Int. J. Mol. Sci. 20, 999 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Hu, W. et al. Neutrophil extracellular traps facilitate cancer metastasis: cellular mechanisms and therapeutic strategies. J. Cancer Res. Clin. Oncol. 149, 2191–2210 (2023).

    Article  PubMed  Google Scholar 

  190. Liu, Y. F. 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).

    Article  PubMed  Google Scholar 

  191. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wang, Y. et al. Targeting myeloid-derived suppressor cells in cancer immunotherapy. Cancers 12, 2626 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Xiang, H. et al. Cancer-associated fibroblasts promote immunosuppression by inducing ROS-generating monocytic MDSCs in lung squamous cell carcinoma. Cancer Immunol. Res. 8, 436–450 (2020).

    Article  CAS  PubMed  Google Scholar 

  194. Hotchkiss, K. A. et al. Mechanisms by which tumor cells and monocytes expressing the angiogenic factor thymidine phosphorylase mediate human endothelial cell migration. Cancer Res. 63, 527–533 (2003).

    CAS  PubMed  Google Scholar 

  195. Robinson, A., Han, C. Z., Glass, C. K. & Pollard, J. W. Monocyte regulation in homeostasis and malignancy. Trends Immunol. 42, 104–119 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Mendoza-Reinoso, V., McCauley, L. K. & Fournier, P. G. J. Contribution of macrophages and T cells in skeletal metastasis. Cancers 12, 1014 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Radtke, A. J. et al. IBEX: an iterative immunolabeling and chemical bleaching method for high-content imaging of diverse tissues. Nat. Protoc. 17, 378–401 (2022).

    Article  CAS  PubMed  Google Scholar 

  199. Alberti, D., Guarniero, M., Maciola, A. K., Dotta, E. & Pasqual, G. Engineering ligand and receptor pairs with LIPSTIC to track cell–cell interactions. Curr. Protoc. 1, e311 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank S. Kaczanowska, C. Contreras and all members of the Kaplan laboratory for their editing of this Review; and thank S. Morrison for helpful discussions.

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  1. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Kailey N. Jackett, Alice T. Browne, Etan R. Aber, Miranda Clements & Rosandra N. Kaplan

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Jackett, K.N., Browne, A.T., Aber, E.R. et al. How the bone microenvironment shapes the pre-metastatic niche and metastasis. Nat Cancer 5, 1800–1814 (2024). https://doi.org/10.1038/s43018-024-00854-6

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