PTEN-AKT2 regulates mixed lineage liver cancer development and sensitizes cancer cells to TGFβ treatment

Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.