Article ; Online: KIT promotes tumor stroma formation and counteracts tumor-suppressive TGFβ signaling in colorectal cancer.
2022 Volume 13, Issue 7, Page(s) 617
Abstract: 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 ... ...
| Abstract | 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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| MeSH term(s) | Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; Humans ; Proto-Oncogene Proteins c-kit/metabolism ; Signal Transduction ; Transforming Growth Factor beta/metabolism ; Tumor Microenvironment |
| Chemical Substances | Transforming Growth Factor beta ; KIT protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2022-07-16 |
| Publishing country | England |
| Document type | Journal Article |
| ZDB-ID | 2541626-1 |
| ISSN | 2041-4889 ; 2041-4889 |
| ISSN (online) | 2041-4889 |
| ISSN | 2041-4889 |
| DOI | 10.1038/s41419-022-05078-z |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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