The Archibald Assistant Professor of Cancer Biology, Assistant Professor of Biological Sciences at the University of Notre Dame
University of Notre Dame
Genetic models of pancreatic cancer
Pancreatic Ductal Adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in the United States and has a 5-year survival rate of 8%. This dismal prognosis shows an urgent need for novel therapeutic strategies. A prominent desmoplastic reaction, when the microenvironment surrounding epithelial tumors expands due to infiltration of fibroblasts, pancreatic stellate cells, immune cell populations, and endothelial cells, is one of the hallmarks of PDAC. This dense stromal layer can account for up to 90% of the tumor bulk and is believed to serve as a physical impediment to effective pharmacological treatment and to play an important role in the aggressive nature of the disease. Thus, full understanding of disease development will require experimental assessment of the mechanisms through which the microenvironment can affect the course of disease progression.
The Hill lab uses novel mouse models, human clinical samples, and newly-established assay systems to elucidate how the microenvironment or inflammation contributes to all three stages of tumorigenesis: initiation, progression, and therapeutic resistance.
The lab’s current focus is on three questions which have implications beyond pancreatic cancer research: (i) How does the microenvironment influence metastasis development? (ii) How does endoplasmic reticulum (ER) stress contribute to tumor growth and maintenance? (iii) How do exosomes from the microenvironment regulate chemoresistance in epithelial tumor cells?
Novel therapeutic targets and strategies identified from these projects will have immediate clinical relevance and could potentially change the current treatment strategies for patients with advanced stage pancreatic cancer.
Dr. Hill was a Damon Runyon postdoctoral fellow at the University of California, Los Angeles, in the lab of Dr. Hong Wu. His doctorate in Genetics and Molecular Biology is from the University of North Carolina at Chapel Hill where he worked in the lab of Dr. Terry Van Dyke.
Zeleniak A*, Huang W*, Fishel M, and Hill R. PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma. Neoplasia. 2017 Nov 22;20(1):12-24. doi: 10.1016/j.neo.2017.10.004.
Gifford J and Hill R. GRP78 Influences Chemoresistance and Prognosis in Cancer. Current Drug Targets 2017 Jun Volume: 18 (E-pub Abstract Ahead of Print) DOI: 10.2174/1389450118666170615100918.
Zeleniak A, Huang W, Brinkman M, Fishel M, and Hill R. Loss of MTSS1 Results in Increased Metastatic Potential in Pancreatic Cancer. Oncotarget 2017 Mar 7;8(10):16473-16487. doi: 10.18632/oncotarget.14869.
Richards K, Zeleniak A, Fishel M, Wu J, Littlepage L, and Hill R. Cancer-Associated Fibroblast Exosomes Regulate Survival and Proliferation of Pancreatic Cancer Cells. Oncogene 2017 Mar 30;36(13):1770-1778. doi: 10.1038/onc.2016.353. Epub 2016 Sep 26.
Gifford J, Huang W, Zeleniak A, Hindoyan A, Wu H, Donahue T, and Hill R. Expression of GRP78, Master Regulator of The Unfolded Protein Response, Increases Chemoresistance In Pancreatic Ductal Adenocarcinoma. Molecular Cancer Therapeutics 2016 May;15(5):1043-1052
Taller D, Richards K, Slouka Z, Senapati S, Hill R, Go D, and Chang H. On-Chip Surface Acoustic Wave Lysis and Ion-Exchange Nanomembrane Detection of Exosomal RNA for Pancreatic Cancer Study and Diagnosis. Lab on a Chip2015 Apr 7;15(7):1656-66. (Cover)
Hill R, Li Y, Tran L, Garcia A, Hargan J, Kim C, Wang Y, Dry S, Donahue T, Herschman H, and Wu H. Delayed progression of pancreatic cancer development through cell-intrinsic activity of Cox-2. Molecular Cancer Therapeutics2012 Oct11(10):2127-2137. (Cover)
Donahue T, Tran L, Hill R, Li Y, Kovochich, Calvopina J, Patel S, Hindoyan A, Farrell J, Li X, Dawson D, and Wu H. An Integrative Survival-Based Genomic and Molecular Profile of Human Pancreatic Cancer. Clinical Cancer Research. 2012 Mar 1;18(5):1352-63.
Hill R, Hargan J, Kim C, Wang Y, Dawson D, Donahue T, Dry S, and Wu H. PTEN Loss Accelerates KrasG12D-Induced Pancreatic Cancer Development. Cancer Research. 2010 Sep 15;70(18):7114-24.
Hill R and Wu H. PTEN, Stem Cells, and Cancer Stem Cells. Journal of Biological Chemistry. 2009 May 1;284(18):11755-9.
Hill R, Song Y, Cardiff R, and Van Dyke T. Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell. 2005 Dec 16;123(6):1001-11. (Cover)
Hill R, Song Y, Cardiff R, and Van Dyke T. Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model. Cancer Research. 2005 Nov 15;65(22):10243-54.
• Bierie B, Moses HL. Under pressure: stromal fibroblasts change their ways. Cell. 2005 Dec 16;123(6):985-7.