Function of mutant IDH in cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is an invasive cancer of the liver bile ducts and is among the most lethal of all human malignancies. It is the second most common type of primary liver tumor and has been rising in incidence worldwide for the past 3 decades. These tumors exhibit a high rate of mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes. These mutations result in a novel enzymatic function: while the wild type enzyme catalyzes conversion of isocitrate to α-ketoglutarate (αKG), mutant IDH leads to the reduction of αKG to R(–)-2-hydroxyglutarate (2-HG). 2-HG inhibits the function of the family of dioxygenase enzymes that utilize αKG as a cofactor, including epigenetic modifiers JmjC family histone demethylases and TET family dioxygenases that mediate DNA demethylation. Recently, we demonstrated that mutant IDH is a specific regulator of the hepatic regenerative response that facilitates progenitor cell activation via silencing HNF4α, which encodes a master regulator of hepatocyte identity and quiescence. By blocking differentiation of these hepatic progenitors, mutant IDH creates a cell population primed for oncogenic transformation. Our present focus is to decipher the metabolic and epigenetic circuitry underlying these phenotypes and to identify vulnerabilities of IDH mutant cancer cells that will inform new therapeutic strategies for this deadly disease.
Metabolic reprogramming in pancreatic cancer
Pancreatic ductal adenocarcinomas (PDA) must contend with particularly severe metabolic stress as the hypovascular, fibrotic tumor microenvironment results in extreme hypoxia and limited nutrient availability. In turn, a number of acquired alterations in nutrient acquisition and utilization are required for pancreatic growth and survival. These include increasing glucose uptake, scavenging of serum lipids and proteins from the extracellular space, and activation of autophagy, a process of recycling cellular components through engulfment in modified membranes and degradation in lysosomes. Many of these adaptive changes in metabolism may represent important nodes that could be targeted for therapeutic intervention. Recent work from our laboratory has sought to uncover the molecular programs underlying metabolic reprogramming in PDA. We have defined an aberrantly activated transcriptional network driving increased function of the autophagy-lysosome system that is required to maintain energy homeostasis in PDA. Additional projects focus on deciphering the impact of mutations in key PDA genes on metabolic circuitry of tumor cells, and studying regulation of tumor metabolism as barrier for progression of benign precursors to malignant cancer.
Development of Liver Cancer Model Systems and Therapeutic Discovery
Although ICC’s are highly aggressive and increasing in incidence, their pathogenesis remains poorly understood. Recent studies have revealed considerable genetic heterogeneity between individual tumors, including mutations in IDH1/2, and have indicated considerable genetic heterogeneity between individual tumors. A key limitation in the field includes a paucity of experimental systems with which to define the contributions of the lesions to biliary cancer progression. We have established a series of genetically engineered mouse models that incorporate combinations of the major mutations found in the human disease. In addition, our ongoing efforts include the development of a human ICC xenograft and primary cell line bank and the use of these systems for genetic and small-molecule screening in genetically defined subtypes of this cancer.The Hippo pathway is a conserved regulator of organ size. We have shown that this pathway is central for controlling the quiescence of liver progenitor cells, and that its loss leads to massive liver overgrowth and development of both major types of liver cancer (hepatocellular carcinoma and ICC). The lab is studying the key molecular mediators of tumorigenesis controlled by the Hippo pathway, determining the contribution of Hippo deregulation to subtypes of human liver cancer, and establishing approaches to target it therapeutically.