BRAF inhibition increases TGFβ2 production and stimulates metastasis in mice with endogenous BRAFV600E-induced hepatocellular carcinoma

• 成果类型: Article
• 署名作者: Cisowski, Jaroslaw; Zowalaty, Ahmed Ezat El; Sayin, Sama I.; Czarnota, Piotr; Gromowski, Tomasz; Eklund, Ella A.; Kashif, Muhammad; Patel, Angana A. H.; Molinaro, Antonio; Lindahl, Per; Wiel, Clotilde; Sayin, Volkan I.; Bergo, Martin O.; Barbacid, Mariano
• 署名单位: University of Gothenburg; Jagiellonian University; University of Gothenburg; University of Gothenburg; University of Gothenburg; Sahlgrenska University Hospital; Jagiellonian University; Karolinska Institutet; University of Gothenburg; Sahlgrenska University Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2503044122
• 发表日期: 2025-11-11
• 页码: e2503044122
• 关键词: oncogenes; tumor suppressors; targeted therapy; liver; braf; PATHWAY; GROWTH; ras; TRANSFORMATION; expression; protein; MODEL

摘要

The MEK-ERK pathway is a key driver of hepatocellular carcinoma (HCC) pathogenesis, and BRAF mutations, particularly BRAFV600E, can contribute to its activation. Although BRAFV600E mutations are rare in human HCC, they do occur, yet their physiologic impact in liver cells, especially when combined with frequent comutations in tumor suppressor genes, remains poorly understood. Moreover, the effect of BRAF inhibitors on HCC progression and metastasis is not well-defined. Therefore, we developed mouse models with hepatocyte-specific BRAFV600E expression and Trp53 or Cdkn2a deletion to assess tumor development, subtypes, and metastatic patterns. We found that BRAFV600E expression caused hepatomegaly, vascular congestion, and ductal reactions, and led to reduced liver function and early mortality. Codeletion of Trp53 or Cdkn2a markedly increased primary liver tumor incidence and enabled sarcomatoid metastasis. While the BRAF inhibitor PLX4720 effectively reduced primary tumors and extended survival, it paradoxically increased sarcomatoid metastases. Mechanistically, PLX4720 and other RAF inhibitors induced TGF(32 expression which promoted epithelial-to-mesenchymal transition (EMT) and enhanced tumorigenicity. The effects of RAF inhibitors on TGF(32 expression were validated in BRAFV600E-mutant human melanoma cells. We conclude that BRAFV600E drives diverse primary tumors but only one type of metastasis and that RAF inhibition, while effective against primary tumors, may promote metastasis through TGF(32-mediated EMT. Although RAF inhibitors remain promising therapies, their unintended role in enhancing metastasis raises concerns that may extend beyond liver cancer to other BRAFV600E-driven malignancies.