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Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression
Wen-Hao Hsu1, Kyle A LaBella1, Yiyun Lin2
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discovery
|September 28, 2023
Summary
Oncogenic KRAS transforms fibroblasts into lipid-rich cells that promote colorectal cancer growth and spread. Targeting the KRAS-TFCP2-VEGFA pathway inhibits tumor angiogenesis and progression, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Oncogenic KRAS (KRAS*) drives colorectal cancer (CRC) progression by suppressing antitumor immunity and promoting invasion.
- KRAS* plays a role in modulating the tumor microenvironment, influencing cancer hallmarks.
Purpose of the Study:
- To investigate the role of KRAS* in transforming carcinoma-associated fibroblasts (CAFs) within the tumor microenvironment.
- To elucidate the molecular mechanisms by which KRAS* promotes angiogenesis and tumor progression in CRC.
- To identify potential therapeutic targets for KRAS*-driven CRC.
Main Methods:
- Utilized KRAS*-driven colorectal cancer mouse models.
- Investigated the activation of transcription factor CP2 (TFCP2) by KRAS*.
- Analyzed the upregulation of BMP4 and WNT5B expression.
- Assessed the production of VEGFA by lipid-rich CAFs.
- Employed genetic and pharmacologic neutralization of TFCP2.
- Correlated findings with human colorectal cancer patient data.
Main Results:
- KRAS* transforms CAFs into lipid-laden CAFs, which promote angiogenesis and tumor progression.
- KRAS* activates TFCP2, upregulating BMP4 and WNT5B, leading to CAF lipid accumulation.
- Lipid-rich CAFs produce VEGFA, driving tumor angiogenesis.
- Neutralization of TFCP2 in mouse models reduced lipid-rich CAFs, decreased angiogenesis, and improved survival.
- Lipid-rich CAF and TFCP2 signatures correlate with poor prognosis in human CRC.
Conclusions:
- KRAS* reprograms CAFs into a pro-angiogenic, lipid-rich phenotype via the TFCP2-BMP4/WNT5B axis.
- This KRAS*-induced CAF transformation drives tumor angiogenesis and progression in colorectal cancer.
- Targeting the KRAS*-TFCP2-VEGFA axis represents a promising therapeutic strategy for KRAS*-driven CRC.
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