Research & Projects

Our lab studies molecular genetics and signaling pathways during liver cancer growth to develop new therapies to treat liver cancer. We are studying multiple types of liver cancer, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and hepatoblastoma (HB).

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PI3K/Pten/AKT/mTOR signaling cascade in HCC and ICC pathogenesis

Deregulated PI3K/Pten/AKT/mTOR pathway is frequently found in both HCC and ICC samples. We have established multiple murine tumor models with activated PIK3CA mutations, activated AKT or loss of Pten, leading to the activation of mTOR. Using mTOR inhibitors, we are studying the therapeutic potential of these inhibitors for the treatment of HCC and ICC.

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Figure 1. mTORC1/2 inhibitor INK128 effectively inhibits ICC cell growth. (A) Treatment of human ICC cell line KKU156 with INK128 in vitro; (B) Treatment of mouse ICC with INK128 significantly decreased tumor burden in mice

Hippo and Notch signaling cascades in liver cancer development

Both Hippo and Notch signaling cascades are evolutionally conserved pathways and have played critical roles in development, regeneration, and carcinogenesis. Both pathways have been implicated in liver tumor development. We found that Notch is a key downstream effector of Hippo tumor suppressor pathway, and the two pathways regulate liver tumor cell differentiation status.

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Figure 2. Notch signaling is required for ICC development. (A) Expression of Notch pathway genes in human ICC samples by immunohistochemical staining; (B) blocking Notch signaling by co-expression dominant negative form of RBP-J (dnRBP-J) prevented ICC-like lesion development in AKT/Ras drive mouse liver tumor model.

Metabolic pathways in hepatic carcinogenesis

Aberrant metabolism is a hallmark of cancer. Our lab studies how glucose and fatty acid catabolism pathways are deregulated during liver tumor development and how these metabolic pathways contribute to hepatocarcinogenesis.

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Figure 3: Increased lipogenesis in c-Myc induced mouse HCC. (A) H&E, Oil Red O (lipid droplet), and immunohistochemical (IHC) staining of FASN in wildtype (WT) normal liver and c-Myc HCC tissues. Inset: the expanded view of the yellow box. (B) Rate of de novo lipogenesis measured by 2H2O labeling in wildtype (WT) liver and c-Myc HCC tissues.