Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression

Authors

Wen-Hao Hsu
Kyle A LaBella
Yiyun Lin
Ping Xu
Rumi Lee
Cheng-En Hsieh
Lei Yang
Ashley Zhou
Jonathan M Blecher
Chang-Jiun Wu
Kangyu Lin
Xiaoying Shang
Shan Jiang
Denise J Spring
Yan Xia
Peiwen Chen
John Paul Shen
Scott Kopetz
Ronald A DePinho

Publication Date

12-12-2023

Journal

Cancer Discovery

Abstract

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer, KRAS* suppresses antitumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAF) into lipid-laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) that upregulates the expression of the proadipogenic factors BMP4 and WNT5B, triggering the transformation of CAFs into lipid-rich CAFs. These lipid-rich CAFs, in turn, produce VEGFA to spur angiogenesis. In KRAS*-driven colorectal cancer mouse models, genetic or pharmacologic neutralization of TFCP2 reduced lipid-rich CAFs, lessened tumor angiogenesis, and improved overall survival. Correspondingly, in human colorectal cancer, 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 colorectal cancer.

Keywords

Animals, Humans, Mice, Angiogenesis, Cancer-Associated Fibroblasts, Colonic Neoplasms, Colorectal Neoplasms, DNA-Binding Proteins, Fibroblasts, Lipids, Proto-Oncogene Proteins p21(ras), Transcription Factors, Tumor Microenvironment

Comments

Supplementary Materials

PMID: 37768068