Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression
Menée à l'aide de lignées cellulaires, d'organoïdes et de modèles murins de cancer colorectal, cette étude met en évidence un mécanisme par lequel la GTPase KRAS, en déclenchant la transformation des fibroblastes associés au cancer en fibroblastes riches en lipides, favorise l'angiogenèse et la progression de la tumeur
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.
Cancer Discovery 2023