{"doi":"10.1158/2159-8290.cd-22-1467","title":"Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression","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.","journal":"Cancer Discovery","year":2023,"id":316110,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":116,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":299138,"name":"Kyle A. LaBella","orcid":"0000-0002-0473-9262","position":1,"is_corresponding":false},{"id":232964,"name":"Yiyun Lin","orcid":"0000-0002-9277-3048","position":2,"is_corresponding":false},{"id":505946,"name":"Ping Xu","orcid":"0000-0002-3771-4758","position":3,"is_corresponding":false},{"id":661513,"name":"Rumi Lee","orcid":"0000-0002-5732-9179","position":4,"is_corresponding":false},{"id":809132,"name":"Cheng‐En Hsieh","orcid":"0000-0002-2038-4537","position":5,"is_corresponding":false},{"id":1018808,"name":"Lei Yang","orcid":"0000-0001-9858-5438","position":6,"is_corresponding":false},{"id":1018809,"name":"Ashley Zhou","orcid":"0009-0009-7672-6370","position":7,"is_corresponding":false},{"id":1018810,"name":"Jonathan M. Blecher","orcid":"0009-0009-8975-8718","position":8,"is_corresponding":false},{"id":1884,"name":"Chang‐Jiun Wu","orcid":"0000-0001-8350-6397","position":9,"is_corresponding":false},{"id":1018811,"name":"Kangyu Lin","orcid":"0000-0003-0140-2557","position":10,"is_corresponding":false},{"id":274885,"name":"Xiaoying Shang","orcid":"0009-0004-2398-4855","position":11,"is_corresponding":false},{"id":1018812,"name":"Shan Jiang","orcid":"0000-0002-2042-5298","position":12,"is_corresponding":false},{"id":243058,"name":"Denise J. Spring","orcid":"0000-0002-4593-0901","position":13,"is_corresponding":false},{"id":1018813,"name":"Yan Xia","orcid":"0000-0001-6935-6038","position":14,"is_corresponding":false},{"id":243053,"name":"Peiwen Chen","orcid":"0000-0002-8129-9328","position":15,"is_corresponding":false},{"id":308739,"name":"John Paul Shen","orcid":"0000-0003-4588-2775","position":16,"is_corresponding":false},{"id":241627,"name":"Scott Kopetz","orcid":"0000-0001-9647-3416","position":17,"is_corresponding":false},{"id":7904,"name":"Ronald A. DePinho","orcid":"0000-0002-5625-577X","position":18,"is_corresponding":false},{"id":243054,"name":"Wen‐Hao Hsu","orcid":"0000-0001-9050-8227","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T01:06:32.274501Z","pmid":"37768068","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}