BRAF inhibition increases TGFb2 production and stimulates metastasis in mice with endogenous BRAFV600E-induced hepatocellular carcinoma

Background & Aims: The MEK-ERK pathway plays a crucial role in hepatocellular carcinoma (HCC) pathogenesis, and BRAF mutations can contribute to its activation. While BRAF mutations, particularly BRAFV600E, are rare in human HCC, their effects when expressed physiologically in liver cells, especially in combination with high-incidence co-mutations in tumor suppressor genes, remain poorly understood in immunocompetent mouse models. Moreover, the impact of BRAF inhibitors on HCC progression, especially metastasis, is not well-defined. Here, we study the role of endogenous BRAFV600E expression in liver tumorigenesis and the effect of RAF inhibition on progression and metastasis. Overall design: Methods: We developed mouse models with hepatocyte-specific BRAFV600E expression and Trp53 or Cdkn2a deletion to assess tumor development, subtypes, and metastatic patterns. BRAF inhibitor PLX4720 effects on tumor growth and metastasis were evaluated, and cell lines were established to explore underlying mechanisms.