Journal Article

DKFZ-2025-00737

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CDX2 downregulation regulates intrinsic WNT pathway activation, dictating metastasis in APC and CTNNB1 wildtype colorectal cancer.

Wouters, V. M. ; Helderman, R. F. C. P. A. ; Cameron, K. ; van der Hooff, S. R. ; Torang, A. ; van den Bergh, S. ; Jackstadt, R.DKFZ* ; Sansom, O. J. ; van Neerven, S. M. ; Medema, J. P.

2025
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41388-025-03365-5

Abstract: Colorectal cancer (CRC) can be divided into 4 subtypes of which consensus molecular subtype 4 (CMS4) is associated with metastasis and poor survival. Previously, we reported that the KPN mouse model resembles human CMS4. Strikingly, although tumor formation in this model is slow and limited, effective metastasis is observed. To understand this aggressive behavior, we compared two distinct in vitro KPN models, organoids and tumoroids. The organoid model only carries the original mutations, while the tumoroids are derived from in vivo grown tumors that underwent selection during development. Here, we reveal that tumoroids harbor endogenous WNT pathway activity, which can be driven by tankyrase activity and Cdx2 downregulation. Importantly, WNT pathway activation was heterogeneous in nature, subject to regulation and allowed for a mixture of WNT-driven and YAP-driven cells within tumoroids. This unique type of WNT pathway activation is not crucial for colonic tumor growth, but results in metastatic spreading. Intriguingly, these findings reflect a specific subset of aggressive human CMS4 cancers that display low CDX2 expression and lack of classical WNT pathway mutations, while having a higher tendency to metastasize. Together, these data propose a novel mechanism for WNT pathway activation that drives metastasis formation in aggressive CRC.

Note: 2025 Jul;44(25):2091-2102

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Contributing Institute(s):

1. NWG Tumorprogression und Metastasierung (A013)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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