Loss of colonic fidelity enables multilineage plasticity and metastasis

Patrizia Cammareri, Michela Raponi, Yourae Hong, Caroline V. Billard, Nat Peckett, Yujia Zhu, Fausto D. Velez-Bravo, Nicholas T. Younger, Donnchadh S. Dunican, Sebastian Ö.-G. Pohl, Aslihan Bastem Akan, Nora J. Doleschall, John Falconer, Mark White, Jean Quinn, Kathryn Pennel, Roberta Garau, Sudhir B. Malla, Philip D. Dunne, Richard R. Meehan, Owen J. Sansom, Joanne Edwards, Malcolm G. Dunlop, Farhat V. N. Din, Sabine Tejpar, Colin W. Steele and Kevin B. Myant ()
Additional contact information
Patrizia Cammareri: The University of Edinburgh, Western General Hospital
Michela Raponi: The University of Edinburgh, Western General Hospital
Yourae Hong: Katholieke Universiteit Leuven
Caroline V. Billard: The University of Edinburgh, Western General Hospital
Nat Peckett: The University of Edinburgh, Western General Hospital
Yujia Zhu: The University of Edinburgh, Western General Hospital
Fausto D. Velez-Bravo: Katholieke Universiteit Leuven
Nicholas T. Younger: The University of Edinburgh, Western General Hospital
Donnchadh S. Dunican: The University of Edinburgh, Western General Hospital
Sebastian Ö.-G. Pohl: The University of Edinburgh, Western General Hospital
Aslihan Bastem Akan: The University of Edinburgh, Western General Hospital
Nora J. Doleschall: The University of Edinburgh, Western General Hospital
John Falconer: Cancer Research UK Scotland Institute
Mark White: Cancer Research UK Scotland Institute
Jean Quinn: University of Glasgow
Kathryn Pennel: University of Glasgow
Roberta Garau: The University of Edinburgh, Western General Hospital
Sudhir B. Malla: Cancer Research UK Scotland Institute
Philip D. Dunne: Cancer Research UK Scotland Institute
Richard R. Meehan: The University of Edinburgh, Western General Hospital
Owen J. Sansom: Cancer Research UK Scotland Institute
Joanne Edwards: University of Glasgow
Malcolm G. Dunlop: The University of Edinburgh, Western General Hospital
Farhat V. N. Din: The University of Edinburgh, Western General Hospital
Sabine Tejpar: Katholieke Universiteit Leuven
Colin W. Steele: Cancer Research UK Scotland Institute
Kevin B. Myant: The University of Edinburgh, Western General Hospital

Nature, 2025, vol. 644, issue 8076, 547-556

Abstract: Abstract Cancer cell plasticity enables the acquisition of new phenotypic features and is implicated as a major driver of metastatic progression1,2. Metastasis occurs mostly in the absence of additional genetic alterations3–5, which suggests that epigenetic mechanisms are important6. However, they remain poorly defined. Here we identify the chromatin-remodelling enzyme ATRX as a key regulator of colonic lineage fidelity and metastasis in colorectal cancer. Atrx loss promotes tumour invasion and metastasis, concomitant with a loss of colonic epithelial identity and the emergence of highly plastic mesenchymal and squamous-like cell states. Combined analysis of chromatin accessibility and enhancer mapping identified impairment of activity of the colonic lineage-specifying transcription factor HNF4A as a key mediator of these observed phenotypes. We identify squamous-like cells in human patient samples and a squamous-like expression signature that correlates with aggressive disease and poor patient prognosis. Collectively, our study defines the epigenetic maintenance of colonic epithelial identity by ATRX and HNF4A as suppressors of lineage plasticity and metastasis in colorectal cancer.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-025-09125-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:644:y:2025:i:8076:d:10.1038_s41586-025-09125-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-025-09125-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().