It is argued that formation of a tumour-intrinsic niche is a prerequisite for BRAF-mutant CRC seeding to distant organs and that interference with niche formation may help avoid metastatic relapse.
Abstract
Colorectal cancer (CRC) progression is characterised by a remarkable increase in plasticity and cellular heterogeneity1,2. The ability of cells to shift states and adopt mixed lineage potential exacerbates during metastasis and associates with poor patient survival3. How these atypical differentiated states emerge and drive cancer progression however has remained unclear. Here, we investigate this issue for BRAF-mutant CRC that commonly arise via the serrated pathway4 and are linked to poor prognosis via incompletely understood progression steps. Using patient-derived organoids, gene editing and murine tumour models, we show that mutations in RNF43, a regulator of WNT receptor abundance5, endow BRAF-mutant CRC with metastatic capacity by driving a non-dividing tumour-intrinsic niche cell (TINC) state that provides growth factor self-sufficiency to the cancer tissue. TINCs are enriched in RNF43-mutant, mucinous and metastatic samples of human CRC, and ablation of TINCs lead to re-acquired external growth factor dependency during CRC organoid outgrowth. Together, our findings uncover a mechanism by which tumours leverage cellular plasticity to mediate self-organised stem– and niche-cell interactions. Our results argue that formation of a tumour-intrinsic niche is a prerequisite for BRAF-mutant CRC seeding to distant organs and that interference with niche formation may help avoid metastatic relapse.
It is demonstrated that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1+ tumor stem cells.
A G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy is uncovered, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity.
Cenk Celik, William A. Weston, Thais de Moraes-Lacerda et al.· Genome Medicine· 1 citation
The immortalized non-tumorigenic breast epithelial cell line (MCF10A) develops neoplastic clones under fluctuating conditions in-vitro that mimic the harsh tumor microenvironment and is identified as a potential therapeutic target against epithelial-mesenchymal plasticity and metastatic spread in breast cancer.
Erez Persi, Rafael R. Canevarolo, P. Sudalagunta et al.· Research Square· 1 citation
BACKGROUND & AIMS
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
M. Mastel, A. Guiseris Martinez, Umberto Pozza et al.· Gastroenterology· 0 citations
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 0 citations
These findings indicate that fibroblasts redirect chemotherapy responses toward a stress-adaptive, persister-like phenotype and establish fibroblast-containing 3D melanoma spheroids as a physiologically relevant platform for studying tumour microenvironment-mediated chemotherapy tolerance and stromal-tumour interactions.
Ilie-Ovidiu Pavel, G. Negrea, S. Mészáros et al.· bioRxiv· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
MIT News · Artificial Intelligence· news.mit.eduAug 17, 2026
