Mechanisms that clear mutations drive field cancerization in mammary tissue

Marta Ciwinska, Hendrik A. Messal, Hristina R. Hristova, Catrin Lutz, Laura Bornes, Theofilos Chalkiadakis, Rolf Harkes, Nathalia S.M. Langedijk, Stefan J. Hutten, Renée X. Menezes, Jos Jonkers, Stefan Prekovic, Marja van Oirsouw, Ellen Verschuur, Donna Pinto, Deborah Collyar, Hilary Stobart, Proteeti Bhattacharjee, Daniel Rea, Lodewyk F.A. WesselsMarjanka Schmidt, Esther H. Lips, Fariba Behbod, Jacco van Rheenen*, Jos Jonkers, E. Shelley Hwang, Nicholas E. Navin, Andrew Futreal, Helen R. Davies, Elinor J. Sawyer, Serena Nik-Zainal, Alastair M. Thompson, Jelle Wesseling, Benjamin D. Simons*, Colinda L.G.J. Scheele*,

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1–3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1−/−;Trp53−/− cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.

Original languageEnglish
Pages (from-to)198-206
Number of pages9
JournalNature
Volume633
Issue number8028
DOIs
Publication statusPublished - 5 Sept 2024

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