AKT2 loss inhibits mixed lineage liver malignancy induced by PTEN loss involving TGFb-Notch-SOX9 signal

Primary liver malignancies-including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)-originate from the oncogenic conversion of hepatocytes and cholangiocytes, respectively. Loss or attenuation of phosphatase and tensin homolog (PTEN), a critical negative regulator of the PI3K-AKT signaling axis, is frequently observed in roughly 70% of CCA and 50% of HCC cases. Intriguingly, the incidence of PTEN mutations is approximately doubled in tumors manifesting a combined HCC-CCA phenotype relative to tumors classified as either HCC or CCA alone. Using lineage-specific liver-specific PTEN-deficient mouse models, we show that PTEN loss drives cellular dedifferentiation and oncogenic progression, a process that exhibits strict dependence on AKT2. Mechanistically, we show that PTEN deficiency induces upregulation of NOTCH and SOX9 signal, with SOX9 playing important roles in tumor cell transformation. Furthermore, PTEN loss deficiency enhances the susceptibility of tumor cells to TGFbeta, with TGFbeta treatment repressing the expression of SOX9 in the absence of PTEN. Together, our study identifies PTEN-AKT2 signaling as a key regulator of hepatocyte lineage fidelity and reveals how its disruption enables the reprogramming of mature hepatocytes or cholangiocytes into liver cancer stem cells (LCSCs). We further delineate the cooperative interplay between NOTCH and TGFbeta pathways in PTEN loss-driven liver tumorigenesis.