| First Author | Hsu WH | Year | 2023 |
| Journal | Cancer Discov | Volume | 13 |
| Issue | 12 | Pages | 2652-2673 |
| PubMed ID | 37768068 | Mgi Jnum | J:343569 |
| Mgi Id | MGI:7565352 | Doi | 10.1158/2159-8290.CD-22-1467 |
| Citation | Hsu WH, et al. (2023) Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression. Cancer Discov 13(12):2652-2673 |
| abstractText | 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. SIGNIFICANCE: This study identified a molecular mechanism contributing to KRAS*-driven colorectal cancer progression via fibroblast transformation in the tumor microenvironment to produce VEGFA driving tumor angiogenesis. In preclinical models, targeting the KRAS*-TFCP2-VEGFA axis impaired tumor progression, revealing a potential novel therapeutic option for patients with KRAS*-driven colorectal cancer. This article is featured in Selected Articles from This Issue, p. 2489. |
