KIT promotes tumor stroma formation and counteracts tumor-suppressive TGFβ signaling in colorectal cancer
Open accessAbstract
Expression profiling has identified four consensus molecular subtypes (CMS1-4) in colorectal cancer (CRC). The receptor tyrosine kinase KIT has been associated with the most aggressive subtype, CMS4. However, it is unclear whether, and how, KIT contributes to the aggressive features of CMS4 CRC. Here, we employed genome-editing technologies in patient-derived organoids (PDOs) to study KIT function in CRC in vitro and in vivo. CRISPR-Cas9-mediated deletion of the KIT gene caused a partial mesenchymal-to-epithelial phenotype switch and a strong reduction of intra-tumor stromal content. Vice versa, overexpression of KIT caused a partial epithelial-to-mesenchymal phenotype switch, a strong increase of intra-tumor stromal content, and high expression of TGFβ1. Surprisingly, the levels of phosphorylated SMAD2 were significantly lower in KIT-expressing versus KIT-deficient tumor cells. In vitro analyses showed that TGFβ signaling in PDOs limits their regenerative capacity. Overexpression of KIT prevented tumor-suppressive TGFβ signaling, while KIT deletion sensitized PDOs to TGFβ-mediated growth inhibition. Mechanistically, we found that KIT expression caused a strong reduction in the expression of SMAD2, a central mediator of canonical TGFβ signaling. We propose that KIT induces a pro-fibrotic tumor microenvironment by stimulating TGFβ expression, and protects the tumor cells from tumor-suppressive TGFβ signaling by inhibiting SMAD2 expression.
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Elevated AKT3 and KIT, reduced mitochondrial respiratory complex I activity, and modified alternative splicing landscape are biological hallmarks of CMS4.
“Among other biological hallmarks of this subtype shown to contribute to CMS4 traits feature elevated AKT3 (42) and KIT (43), reduced mitochondrial respiratory complex I activity (44)—possibly resulting from KIT overexpression (43)—or modified alternative splicing landscape (45).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [43]
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Mouillet-Richard, S., Cazelles, A., Sroussi, M., Gallois, C., Taieb, J., & Laurent-Puig, P. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-3964 · Cited by 43 · see citing works
- Authors
- Küçükköse, E., Peters, N. A., Ubink, I., van Keulen, V. A. M., Daghighian, R., Verheem, A., Laoukili, J., & Kranenburg, O.
- Affiliations
- University Medical Center Utrecht (NL)
- Corresponding author
- Kranenburg, Onno
- Venue
- Cell Death & Disease
- Published
- 2022-07-16
- Volume
- 13
- Issue
- 7
- Pages
- 617-617
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC9288482
- OpenAlex
- W4285605421
- Cited by
- 18
- References
- 45
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 3
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- KIT, colorectal cancer, consensus molecular subtypes, CMS4, TGF-beta signaling, Smad2, tumor stroma, tumor microenvironment, epithelial-mesenchymal transition, mesenchymal-epithelial transition, patient-derived organoids, tumor fibrosis, CRISPR/Cas9 gene deletion
- MeSH terms
- Humans, Colorectal Neoplasms, Signal Transduction, Transforming Growth Factor beta, Proto-Oncogene Proteins c-kit, Tumor Microenvironment
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