Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2023 Dec 12;13(12):2652-2673. doi: 10.1158/2159-8290.CD-22-1467.
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.
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.
致癌 KRAS（KRAS*）有助于许多癌症的特征。在结直肠癌中，KRAS抑制抗肿瘤免疫以促进肿瘤侵袭和转移。在这里，我们揭示了 KRAS将癌相关成纤维细胞（CAF）的表型转化为富含脂质的 CAF，促进血管生成和肿瘤进展。在机制上，KRAS激活转录因子 CP2（TFCP2），上调促脂肪生成因子 BMP4 和 WNT5B 的表达，触发 CAF 向富含脂质的 CAF 转化。这些富含脂质的 CAF 反过来又产生 VEGFA 来刺激血管生成。在 KRAS-驱动的结直肠癌小鼠模型中，TFCP2 的遗传或药理学中和减少了富含脂质的 CAF，减少了肿瘤血管生成，并改善了总体生存。相应地，在人类结直肠癌中，富含脂质的 CAF 和 TFCP2 特征与更差的预后相关。这项工作揭示了 KRAS在转化 CAF、驱动肿瘤血管生成和疾病进展中的新作用，为 KRAS-驱动的结直肠癌提供了一种可行的治疗干预措施。
本研究通过肿瘤微环境中的成纤维细胞转化来产生 VEGFA 驱动肿瘤血管生成，确定了导致 KRAS*-驱动的结直肠癌进展的分子机制。在临床前模型中，靶向 KRAS*-TFCP2-VEGFA 轴可损害肿瘤进展，为 KRAS*-驱动的结直肠癌患者提供了一种潜在的新治疗选择。本文选自本期的重点文章，第 2489 页。
