University of Nebraska Medical Center

Current Projects

Cholangiocarcinoma cell death mechanisms

My lab is focused on cell death in liver cancer, specifically cholangiocarcinoma, a malignant tumor arising in the bile duct epithelium. Clinically, this tumor is very difficult to treat and new treatment options are needed. Resistance of tumor cells to apoptosis upon chemotherapy or targeted therapy is a challenge. Cholangiocarcinoma cells resist apoptotic signaling induced by TRAIL (a tumor surveillance death ligand), both through increased expression of anti-apoptotic microRNAs and through decreased expression of pro-apoptotic microRNAs. Further studies are investigating FGFR4 signaling in malignant disease progression. Decreased apoptosis signaling may impact the response to anti-tumor therapies, and reversing this resistance has the potential to improve treatment of this devastating disease.

Non-alcoholic fatty liver disease

Injury in non-alcoholic fatty liver disease is mediated in part by elevated circulating free fatty acids. Previous work has demonstrated that hepatocytes are sensitive to lipoapoptosis when treated with free fatty acids, contributing to liver disease. We have shown that free fatty acids cause cholangiocyte lipoapoptosis, suggesting that injury to ductular epithelium may contribute to pathology. Other labs have shown that cholangiocyte proliferation correlates with fibrosis and NASH severity. Further, bile duct swelling and loss are also observed in a subset of patients who have a cholestatic NASH presentation. We propose that cholangiocyte injury causes progression and worsening of NASH.

MicroRNA Signaling

I have established a distinct line of investigation into dysregulation of microRNAs in cholangiocarcinoma and the effects on cell death signaling in malignant and non-malignant liver processes. MicroRNA levels are commonly altered in disease and these changes have the potential to affect hundreds of gene targets and significantly influence cell function. For instance, we discovered that Mcl-1 protein levels are decreased by microRNA-mediated silencing, and specifically that miR-29b targets Mcl-1 in cholangiocytes. This regulation is lost in malignant cells which have lower levels of miR-29b. Increasing the cellular miR-29b levels rendered malignant cells sensitive to TRAIL killing.

Additional pathways whereby microRNAs regulate apoptosis are being pursued. This includes regulation of microRNA expression by disease signaling and identification of novel targets of microRNAs. We have data implicating the oncogenic mir-106b~25 cluster in regulating TRAIL death receptor signaling. Additionally we have found that miR-10 has regulatory roles in cancer cells.