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.

  • Research Highlight
  • Published:

Effective immunosurveillance of clonally expanded mammary aneuploid cells

Cellular & Molecular Immunology volume 22, pages 131–133 (2025)Cite this article

Subjects

Access through your institution
Buy or subscribe

Most cancer cells harbor gross chromosomal alterations that result in an aneuploid karyotype. Lin et al. recently demonstrated that mammary epithelia from healthy women contain clonally expanded aneuploid cell populations that share considerable genomic traits with invasive breast tumors, potentially representing malignant precursors that have not yet evaded immunosurveillance [1].

The so-called “three Es” model postulates that the immune system efficiently eliminates newly transformed cells and preserves microscopic tumors in a dynamic equilibrium that prevents outgrowth and metastatic dissemination [2]. In this context, locally invasive and overtly metastatic (hence clinically relevant) neoplasms can only emerge once malignant cells acquire extra genetic or epigenetic alterations that provide them with the ability to evade anticancer immunity [2]. Such an immunoevasive phenotype can emerge from multiple, not necessarily overlapping, mechanisms that reflect the capacity of malignant cells to avoid detection and recognition by immune cells (camouflage), inhibit immune effector functions (coercion), or actively resist immune elimination (cytoprotection), as we have recently conceptualized under a novel “three Cs” framework [3]. Importantly, gross chromosomal rearrangements leading to significant copy number alterations (CNAs) constitute a major substrate for tumor evolution under microenvironmental and immune selective pressures, de facto fostering immune evasion along with intratumoral heterogeneity [4]. While such genomic alterations can result from a variety of mechanisms, whole-genome duplication events followed by defective mitosis in the context of failed oncosuppression by mitotic catastrophe [5] stand out as major sources of chromosomal instability across multiple cancer types, suggesting that tetraploidy is a metastable premalignant state that provides the genetic ground for accelerated tumor progression in the context of failed anticancer immunosurveillance [6, 7].

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1

References

  1. Lin Y, Wang J, Wang K, Bai S, Thennavan A, Wei R, et al. Normal breast tissues harbour rare populations of aneuploid epithelial cells. Nature. 2024. https://doi.org/10.1038/s41586-024-08129-x

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60. https://doi.org/10.1146/annurev.immunol.22.012703.104803

    Article  CAS  PubMed  Google Scholar 

  3. Galassi C, Chan TA, Vitale I, Galluzzi L. The hallmarks of cancer immune evasion. Cancer Cell. 2024;42:1825–63. https://doi.org/10.1016/j.ccell.2024.09.010

    Article  CAS  PubMed  Google Scholar 

  4. Vitale I, Shema E, Loi S, Galluzzi L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat Med. 2021;27:212–24. https://doi.org/10.1038/s41591-021-01233-9

    Article  CAS  PubMed  Google Scholar 

  5. Vitale I, Galluzzi L, Castedo M, Kroemer G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol. 2011;12:385–92. https://doi.org/10.1038/nrm3115

    Article  CAS  PubMed  Google Scholar 

  6. Ganem NJ, Godinho SA, Pellman D. A mechanism linking extra centrosomes to chromosomal instability. Nature. 2009;460:278–82. https://doi.org/10.1038/nature08136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pancancer patterns of somatic copy number alteration. Nat Genet. 2013;45:1134–40. https://doi.org/10.1038/ng.2760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T, Cowing-Zitron C, et al. Mosaic copy number variation in human neurons. Science. 2013;342:632–7. https://doi.org/10.1126/science.1243472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci USA. 2014;111:13409–14. https://doi.org/10.1073/pnas.1415287111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Britt KL, Cuzick J, Phillips KA. Key steps for effective breast cancer prevention. Nat Rev Cancer. 2020;20:417–36. https://doi.org/10.1038/s41568-020-0266-x

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The LG lab is/has been supported (as a PI unless otherwise indicated) by one NIH R01 grant (#CA271915), by two Breakthrough Level 2 grants from the US DoD BCRP (#BC180476P1, #BC210945), by a grant from the STARR Cancer Consortium (#I16--0064), by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (#W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (#CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (#ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative (New York, US), by a pre-SPORE grant (PI: Demaria, Formenti), a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Ed of Radiation Oncology at Weill Cornell Medicine (New York, US), by startup funds from Fox Chase Cancer Center (Philadelphia, US), by industrial collaborations with Lytix Biopharma (Oslo, Norway), Promontory (New York, US) and Onxeo (Paris, France), as well as by donations from Promontory (New York, US), the Luke Heller TECPR2 Foundation (Boston, US), Sotio a.s. (Prague, Czech Republic), Lytix Biopharma (Oslo, Norway), Onxeo (Paris, France), Ricerchiamo (Brescia, Italy), and Noxopharm (Chatswood, Australia). The IV lab is supported by funding from Associazione Italiana per la Ricerca sul Cancro AIRC, IG 2022 ID. 27685), CARESS Fondazione Piemontese per la Ricerca sul Cancro (FRPC) 5 × 1000 Intramural Grant, and startup grants from the Italian Institute for Genomic Medicine and Compagnia di San Paolo.

Author information

Authors and Affiliations

  1. Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    Lorenzo Galluzzi

  2. Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy

    Gwenola Manic & Ilio Vitale

  3. Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    Gwenola Manic & Ilio Vitale

Authors
  1. Lorenzo Galluzzi
    View author publications

    Search author on:PubMed Google Scholar

  2. Gwenola Manic
    View author publications

    Search author on:PubMed Google Scholar

  3. Ilio Vitale
    View author publications

    Search author on:PubMed Google Scholar

Contributions

LG conceived the article. LG and IV wrote the first version of the manuscript with constructive input from GM. GM generated display items under the supervision of LG and IV. All the authors approved the submitted version of the article.

Corresponding authors

Correspondence to Lorenzo Galluzzi or Ilio Vitale.

Ethics declarations

Competing interests

LG holds research contracts with Lytix Biopharma, Promontory, and Onxeo; has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, AbbVie, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation; and holds Promontory stock options. GM and IV have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Galluzzi, L., Manic, G. & Vitale, I. Effective immunosurveillance of clonally expanded mammary aneuploid cells. Cell Mol Immunol 22, 131–133 (2025). https://doi.org/10.1038/s41423-024-01250-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41423-024-01250-x

Search

Advanced search

Quick links