Associate Professor, Biochemistry and Molecular Biology
Phone: 402-559-3177 (Office)
M.D., Saint Louis University, St. Louis, Missouri 2004
Ph.D., Saint Louis University, St. Louis, Missouri 2003
Research Opportunities in my laboratory:
Graduate students considered on an individual basis
Medical students, summer research
Cholangiocarcinoma (liver cancer)
Cholangiocyte injury in non-alcoholic steatohepatitis
MicroRNA expression and function
Apoptosis resistance mechanisms
Sathish Natarajan, Cody Wehrkamp, Justin Mott, Mary Anne Phillippi, Ashley Mohr
Sathish Natarajan, Instructor
Sathish is investigating biliary injury in NASH, including altered apoptotic signaling downstream of the forkhead box transcription factor FoxO3. He is interested in liver pathophysiology and the relationship of liver function with other organ systems.
Ashley Mohr, Postdoctoral Fellow
Ashley is interested in how the microenvironment promotes tumor progression. With experience in tumor models and advanced microscopy, her work has demonstrated new pathways that may be targeted for future therapy.
Cody Wehrkamp, Ph.D. Candidate
Cody is investigating cancer signaling in response to miR-106b, a microRNA that is increased in cholangiocarcinoma. He has investigated miR-106b targets and the functional effects on cell death and tumor progression.
Mary Anne Phillippi, Lab Manager
Mary Anne is the lead surgeon for tumor experiments and has projects in both cancer and NASH model systems. Her efforts have recently uncovered unexpected signaling from free fatty acids in cholangiocytes.
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 the prognosis is poor. In part, this is due to resistance of tumor cells to apoptosis upon chemotherapy or targeted therapy. 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. 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.
I have established a distinct line of investigation into dysregulation of microRNAs in cancer 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. Promising data to date illustrate that miR-25 is antiapoptotic by way of targeting DR4 and antagonism of miR-25 promotes cholangiocarcinoma cell death.
Non-alcoholic fatty liver disease
Injury in non-alcoholic fatty liver disease is mediated in part by elevated concentrations of circulating free fatty acids. Previous work has demonstrated that hepatocytes are sensitive to lipoapoptosis when treated with free fatty acids, contributing to liver disease. The combination of injury and inflammation, termed non-alcoholic steatohepatitis (NASH) is a growing cause of end-stage liver failure and liver transplantation. 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 have extended these observations to show that free fatty acids cause cholangiocyte lipoapoptosis, suggesting that injury to ductular epithelium may contribute to pathology.
Selected Recent Publications
Mohr AM and Mott JL. (2015) Overview of MicroRNA Biology (Invited review). Seminars in Liver Disease, 35(1):3-11.
Natarajan SK, Ingham SA, Mohr AM, Wehrkamp CJ, Ray A, Roy S, Cazanave SC, Phillippi MA, Mott JL. (2014) Saturated free fatty acids induce cholangiocyte lipoapoptosis. Hepatology 60(6):1942-1956.
[Highlighted by the journal in an accompanying editorial]
Wehrkamp CJ, Gutwein AR, Natarajan SK, Phillippi MA, Mott JL. (2014) XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells. PLOS ONE, 9(3):e90238. DOI: 10.1371.
Natarajan SK, Smith MA, Wehrkamp CJ, Mohr AM, Mott JL. (2013) MicroRNA function in human disease. (Invited review) Medical Epigenetics, 1(1):106-115. DOI:10.1159/000356447.
Razumilava N, Bronk SF, Smoot RL, Fingas CD, Werneburg NW, Roberts LR, Mott JL. (2012) miR-25 targets TRAIL death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma. Hepatology, 55(2):465-475.
Mott JL*, Kurita S, Cazanave SC, Bronk SF, Werneburg NW, Fernandez-Zapico ME. (2010) Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, Hedgehog and NF-kappaB. Journal of Cellular Biochemistry, 110(5):1155-64. [*corresponding author]
Mott JL, Kobayashi S, Bronk SF, Gores GJ. (2007) mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene 26(42):6133-40.
Research Grants Awarded
Palmitoleate Protects against Cholangiocyte Lipoapoptosis
P20 GM104320-01A1 PI: Zempleni
Nebraska Center for the Prevention of Obesity Diseases
Within the NPOD Center, Dr. Mott is the PI of Project #1. The goal of this 3-year project is to
determine the role of dietary free fatty acids in protecting against lipoapoptosis in bile duct epithelial cells.
Role of FGFR signaling in cholangiocarcinoma
NE DHHS - LB506 PI: Mott
The long-term goal of this project is to describe altered cell death signaling in
cholangiocarcinoma cells to identify targets that will overcome apoptosis resistance and improve response
Apoptosis Effectors Targeted by Hedgehog-Supported MicroRNAs
R03 DK092263-01 PI: Mott
Goal: This proposal investigated the mechanisms by which Hedgehog signaling controls
expression of the microRNA cluster, mir-106b~mir-25. In addition, the mechanisms by which
miR-106b, miR-93, and miR-25 repress apoptosis-related targets will be explored.
Cholangiocyte microRNAs Regulate Mcl-1 and Cell Death
K01 DK079875-05 PI: Mott
Goals: This career development award was designed to support the PI as a junior investigator of
the mechanisms of dysregulated expression of mir-29b in cholangiocarcinoma and how this results
in overexpression of Mcl-1, rendering this cancer apoptosis-resistant.