Journal Article

DKFZ-2026-02054

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer.

Mastel, M. (First author)DKFZ* ; Guiseris Martinez, A.DKFZ* ; Pozza, U.DKFZ* ; Meier, J.DKFZ* ; Chiotakakos, I.DKFZ* ; Jaun, S.DKFZ* ; Artmann, C.DKFZ* ; Diamante, G.DKFZ* ; Georgakopoulos, N.DKFZ* ; Albrecht, P.DKFZ* ; Petersen, Y.DKFZ* ; Reuter, S.DKFZ* ; Schmitt, B.DKFZ* ; Günther, M. ; Thiran, A.DKFZ* ; Nurfauziah, I.DKFZ* ; Ghezzi, I.DKFZ* ; Ouyang, K. S.DKFZ* ; Milsom, M. D.DKFZ* ; Puschhof, J.DKFZ* ; Reitsam, N. G. ; Boonekamp, K. E.DKFZ* ; Betge, J.DKFZ* ; Ormanns, S. ; Boutros, M.DKFZ* ; Jackstadt, R.-F. (Last author)DKFZ*

2026
Elsevier New York, NY

Abstract: BRAF-mutant colorectal cancer (CRC) is a clinically aggressive subtype arising from the serrated pathway and is associated with poor prognosis and therapy resistance. The mechanisms driving malignant transformation in microsatellite-stable (MSS) BRAF-mutant CRC remain incompletely understood. We aimed to define the role of WNT pathway activation in serrated CRC progression and tumor-immune interactions.We generated multiple genetically engineered mouse models (GEMMs) of BRAF-mutant MSS CRC and complementary organoid-based transplantation models. Genetic alterations in WNT pathway components were functionally interrogated. Tumor development and immune microenvironment remodeling were analyzed using bulk RNA sequencing, single-cell RNA sequencing, CITE-seq, and functional in vivo assays.WNT pathway activation via APC or CTNNB1 mutations, but not RNF43 loss, was required for tumor initiation in BRAF-mutant CRC models. WNT activation induced a molecular subtype shift and suppressed immune response pathways. Mechanistically, WNT signaling suppressed CCL20 expression and remodeled the tumor microenvironment (TME) by promoting immunosuppressive myeloid populations and altering T-cell states. Functional assays demonstrated that WNT activation enhances tumor progression in immunocompetent settings, indicating immune evasion as a key driver of malignant progression.WNT pathway activation is a critical determinant of malignant transformation in BRAF-mutant MSS CRC by enabling immune escape. These findings identify WNT signaling as a central regulator of tumor-immune interactions and a potential therapeutic target in this aggressive CRC subtype.

Keyword(s): WNT signaling ; mouse models ; serrated neoplasia ; tumor microenvironment

Note: #EA:A013#LA:A013# / DKFZ-ZMBH Alliance / #DKTKZFB26# / epub

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Contributing Institute(s):

1. NWG Tumorprogression und Metastasierung (A013)
2. NWG-KKE Translationale Gastrointestinale Onkologie und präklinische Modelle (B440)
3. Signalwege funktionelle Genomik (B110)
4. Experimentelle Hämatologie (A012)
5. NWG Epithel-Mikrobiom-Interaktionen (D300)
6. DKTK HD zentral (HD01)

Research Program(s):

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

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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