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Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression.

Wen-Hao HsuKyle A LaBellaYiyun LinPing XuRumi LeeRodney Cheng-En HsiehLei YangAshley ZhouJonathan M BlecherChang-Jiun WuKangyu LinXiaoying ShangShan JiangDenise J SpringYan XiaPeiwen ChenJohn Paul ShenEdmund S KopetzRonald A DePinho
Published in: Cancer discovery (2023)
Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* suppresses anti-tumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAFs) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) which upregulates the expression of the pro-adipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce vascular endothelial growth factor A (VEGFA) to spur angiogenesis. In KRAS*-driven CRC mouse models, genetic or pharmacological neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human CRC, lipid-rich CAF and TFCP2 signatures correlate with worse prognosis. This work unveils a new role for KRAS* in transforming CAFs, driving tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*-driven CRC.
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