Crypt density and recruited enhancers underlie intestinal tumour initiation

Liam Gaynor, Harshabad Singh, Guodong Tie, Krithika Badarinath, Shariq Madha, Andrew Mancini, Swarnabh Bhattacharya, Mikio Hoshino, Frederic J. Sauvage, Kazutaka Murata, Unmesh Jadhav and Ramesh A. Shivdasani ()
Additional contact information
Liam Gaynor: Dana-Farber Cancer Institute
Harshabad Singh: Dana-Farber Cancer Institute
Guodong Tie: Dana-Farber Cancer Institute
Krithika Badarinath: Dana-Farber Cancer Institute
Shariq Madha: Dana-Farber Cancer Institute
Andrew Mancini: Genentech
Swarnabh Bhattacharya: Dana-Farber Cancer Institute
Mikio Hoshino: National Center of Neurology and Psychiatry
Frederic J. Sauvage: Genentech
Kazutaka Murata: Dana-Farber Cancer Institute
Unmesh Jadhav: Dana-Farber Cancer Institute
Ramesh A. Shivdasani: Dana-Farber Cancer Institute

Nature, 2025, vol. 640, issue 8057, 231-239

Abstract: Abstract Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence1,2. Mutation of Apc, the most common initiating event in conventional adenomas3, activates Wnt signalling, thus conferring fitness on mutant intestinal stem cells (ISCs)4,5. Apc mutations may occur in ISCs that arise by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar6,7, it is unclear whether both generate tumours equally well in uninjured intestines. It is also unknown whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source, but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs that are not associated with adenomas. These cis elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumorigenesis.

Date: 2025
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DOI: 10.1038/s41586-024-08573-9

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