p53 protein degradation redefines the initiation mechanisms and drives transitional mutations in colorectal cancer

Irene Herranz-Montoya, Mariana Angulo-Aguado, Cristian Perna, Sladjana Zagorac, Luis García-Jimeno, Solip Park and Nabil Djouder ()
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Irene Herranz-Montoya: Centro Nacional Investigaciones Oncológicas (CNIO)
Mariana Angulo-Aguado: Centro Nacional Investigaciones Oncológicas (CNIO)
Cristian Perna: IRYCIS
Sladjana Zagorac: Centro Nacional Investigaciones Oncológicas (CNIO)
Luis García-Jimeno: Centro Nacional Investigaciones Oncológicas (CNIO)
Solip Park: Centro Nacional Investigaciones Oncológicas (CNIO)
Nabil Djouder: Centro Nacional Investigaciones Oncológicas (CNIO)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Incidence of colorectal cancer (CRC) is increasing likely due to different mechanisms driving initiation and progression. The initial model proposed by Fearon and Vogelstein posits it as a multi-hit neoplasia, originating from adenomatous-polyps induced by WNT activation, ultimately progressing to aggressiveness through p53 loss. Integrating human data with mouse genetics, we redefine this paradigm, highlighting pivotal roles of MYC, oncogenic URI and p53 degradation to initiate CRC. Early APC loss activates MYC to transcriptionally upregulate URI, which modulates MDM2 activity, triggering p53 proteasomal degradation, essential for tumour initiation and mutation burden accrual in CRC mice. Remarkably, reinstating p53 levels via genetic URI depletion or p53 super-expression in CRC mice with WNT pathway activation prevents tumour initiation and extends lifespan. Our data reveal a “two-hit” genetic model central to APC loss-driven CRC initiation, wherein MYC/URI axis intricately controls p53 degradation, offering mechanistic insights into transitional mutation acquisition essential for CRC progression.

Date: 2025
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DOI: 10.1038/s41467-025-59282-4

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