KIT promotes tumor stroma formation and counteracts tumor-suppressive TGFβ signaling in colorectal cancer

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.

Analyzing aberrant DNA methylation in colorectal cancer uncovered intangible heterogeneity of gene effects in the survival time of patients

“…In addition to the diagnostic role of our identified hub genes such as NKX2-2, KIT, BNDF , and TLE4 in CRC and its sub-types 74 , 85 – 87 , their roles in increasing CRC risk, tumor progression, and targeted therapy have been investigated. For instance, MEF2A 88 and BMP5 89 increase the CRC risk.…”

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research

“…As one of the sharpest and most promising gene editing tools, the CRISPR/Cas9 system has been applied to gene knockout in many types of organoid platforms. In CRC, driver genes such as DACH1 ( Hu et al, 2020 ), LARGE2 ( Dietinger et al, 2020 ), and KIT ( Küçükköse et al, 2022 ) were knocked out by using CRIPSR/CAS9 gene editing technology to investigate the promoting effects of intestinal stemness, cell-matrix adhesion, and phenotype switch in carcinomatosis, respectively. In order to explore the epigenetic contribution in GC, the histone lysine demethylase-1A (KDM1A) gene was knocked out in PDOs, which in turn induced inhibition of Wnt signaling and a strong cell cycle arrest ( Mircetic et al, 2023 ).…”

A Single-Cell Landscape of Spermioteleosis in Mice and Pigs

“…Rbakdn is specifically expressed in the mouse testis, and its expression level continued to increase after the meiosis stage [36]. For pigs, we visualized the differentiating spermatogonial marker genes DMRT1 and KIT [37] (Figure S5I,J). The expression levels of these genes gradually increased over time, and after reaching a peak, their expression levels gradually decreased.…”