The DOI matches its Crossref record; 79 of the 81 references it cites were found in a registry or an index.
Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression
Open accessPublished version of a preprint
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. 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
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“KRAS can alter the phenotype of CAFs, enriching them with lipids, which promotes angiogenesis and tumor progression.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [26]
In the citing paper
“These lipid-enriched CAFs produce VEGFA, fostering angiogenesis and supporting tumor growth [26].”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [26]
In the citing paper
“KRAS activates the transcription factor CP2 (TFCP2), which then stimulates adipocyte differentiation factors, converting CAFs into lipid-rich cells.”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [26]
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Metadata
- Authors
- Hsu, W.-H., LaBella, K. A., Lin, Y., Xu, P., Lee, R., Hsieh, C.-E., Yang, L., Zhou, A., Blecher, J. M., Wu, C.-J., Lin, K., Shang, X., Jiang, S., Spring, D. J., Xia, Y., Chen, P., Shen, J. P., Kopetz, S., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- 3Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2023-09-27
- Volume
- 13
- Issue
- 12
- Pages
- 2652-2673
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC10807546
- OpenAlex
- W4387115132
- Cited by
- 125
- References
- 81
- Citations by year
- 2026: 42 · 2025: 53 · 2024: 28 · 2023: 2
- FWCI
- 15.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP210028)
- National Institutes of Health (F99 CA274661, R01 CA231360)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- oncogenic KRAS, colorectal cancer, cancer-associated fibroblasts, angiogenesis, VEGF-A, TFCP2, BMP4, Wnt5b, tumor microenvironment, tumor progression, antitumor immunity, prognostic signature, KRAS-targeted therapy
- MeSH terms
- Cancer-Associated Fibroblasts, Angiogenesis, Animals, Colonic Neoplasms, DNA-Binding Proteins, Fibroblasts, Humans, Lipids, Transcription Factors, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Mice, Tumor Microenvironment
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