Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression
Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* has been shown to suppress anti-tumor immunity which promotes tumor metastasis. Here, we show that the protumor actions of KRAS* extend to the adipogenic transformation of fibroblasts into lipid-laden cancer-associated fibroblasts (CAFs), which spur angiogenesis. Mechanistically, KRAS*-mediated activation of the transcription factor CP2 (TFCP2) resulted in TFCP2-mediated transcriptional upregulation of pro-adipogenic factors BMP4 and WNT5B to drive lipid-rich CAF transformation. Functionally, these lipid-rich CAFs promoted tumor growth via their production of vascular endothelial growth factor A (VEGFA). Correspondingly, genetic and pharmacological neutralization of TFCP2 decreased the abundance of lipid-rich CAFs, reduced tumor angiogenesis, and increased survival in an autochthonous KRAS*–driven CRC mouse model. These murine findings mirror translational profiles in human CRC. Thus, KRAS* transforms the stromal cell state to promote tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*–driven CRC. Overall design: Three independent samples each from iKAP, iAP, and iKAP-DOXoff (KRAS*-off) CRC tumors were collected for tumor dissociation and single cell sequencing analyses. All tumors were collected in size of 1 cm3 at 2 months after TAM/DOX tumor induction following the procedure described above. For the iKAP-DOXoff (KRAS*-off) CRC tumors, Doxycycline was retrieved for 7 days after 7 weeks of TAM/DOX tumor induction. scRNA Sequencing was performed by MD Anderson's CPRITSingle Core.