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Division of Surgical Oncology
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Bryan C. Fuchs, PhDAssistant Professor of SurgeryHarvard Medical School
Assistant in Molecular BiologyMassachusetts General Hospital
Danielle DePeralta, MDBenjamin Schmidt, MDLan Wei, PhD
We have previously shown that a single nucleotide polymorphism (SNP) in the epidermal growth factor (EGF) gene is associated with an increase risk of developing liver cancer (hepatocellular carcinoma, HCC) in patients with cirrhosis. The EGF SNP is also associated with increased EGF expression and we are currently examining the role of the various cell populations in the liver (i.e. hepatocytes, stellate cells, etc.) on EGF expression and EGF signaling with respect to disease progression. We have also generated several animal models of HCC to determine whether EGF receptor (EGFR) inhibitors, like erlotinib, can inhibit HCC development. Our results suggest that EGFR inhibition prevents the progression of chronic liver disease (i.e. fibrosis and cirrhosis) and therefore inhibits HCC development by reducing the number of preneoplastic nodules through a so-called “field effect.” Erlotinib prevention of HCC can be monitored through traditional histopathology as well as by examining gene expression signatures in the surrounding liver tissue associated with HCC development (this work is done in collaboration with Yujin Hoshida and Todd Golub at the Broad Institute). We are currently using these models to study other prevention strategies as well.
Our ultimate goal is to be able to identify fibrosis and cirrhosis patients at high-risk for HCC development using EGF SNP screening and eventually be able to treat these patients with prevention strategies like those targeting EGFR.
Noninvasive quantification of liver fibrosis would enable early diagnosis of chronic liver disease and provide a means to monitor response to therapy, thus speeding evaluation of novel treatments. In collaboration with Dr. Peter Caravan in the Martinos Center for Biomedical Imaging, we have demonstrated that molecular magnetic resonance imaging (MRI) with a probe specific for Type I collagen can effectively quantify liver fibrosis in animal models. We are now working to translate these findings into human trials as well as examining additional molecular MRI techniques for evaluating liver fibrosis.
Research has shown that cancer cells that have undergone an epithelial-to-mesenchymal transition (EMT) are more resistant to chemotherapy. For example, we have shown that human HCC cell lines that have undergone EMT are more resistant to EGFR-targeted therapies. EMT appears to be a main driver of the common molecular subclasses of HCC and current research in our lab is focused on examining how HCC cells undergo EMT and whether the unique signaling pathways exploited by epithelial and mesenchymal tumors can be used to design novel treatment strategies.
View a list of publications by researchers in the Fuchs Laboratory
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