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2016 Scientific Report

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LORENZO F. SEMPERE, PH.D. Dr. Sempere obtained his B.S. in biochemistry at Universidad Miguel Hernández, Elche, Spain, and earned his Ph.D. at Dartmouth under Victor Ambros. He joined VARI in January 2014 as an Assistant Professor. STAFF HEATHER CALDERONE, PH.D. STEPHANIE GRANT, M.P.A. JENNI WESTERHUIS, M.S.ED., M.S. STUDENTS SHAYNA DONOGHUE DANIELA GOMEZ, B.S. ALYSSA SHEPARD RESEARCH INTERESTS Our laboratory pursues complementary lines of translational research to explain the etiological role of microRNAs and to unravel microRNA regulatory networks during carcinogenesis. We mainly investigate these questions in clinical samples and preclinical models of breast cancer and pancreatic cancer. MicroRNAs can regulate and modulate the expression of hundreds of target genes, some of which are components of the same signaling pathways or biological processes. Thus, functional modulation of a single microRNA can affect multiple target mRNAs (i.e., one drug, multiple hits), unlike therapies based on small interfering RNAs, antibodies, or smallmolecule inhibitors. The laboratory has active projects in the areas of cancer biology and tumor microenvironment, with a translational focus on molecular and cellular heterogeneity and its clinical implications for improving diagnostic applications and therapeutic strategies. Our knowledge of microRNAs is integrated into collaborative efforts with VARI researchers and cores, as well as into new technologies being developed for microRNA studies. Recent work includes the following. We use innovative multiplexed immunohistochemical/in situ hybridization assays to implement diagnostic applications of microRNA biomarkers. Because tissue samples are the direct connection between cancer research and cancer medicine, detailed molecular/cellular characterization of tumors provides the opportunity to translate scientific knowledge into useful clinical information. • Clinically validate tumor compartment–specific expression of the microRNA miR-21 as a prognostic marker for breast cancer. There is a focused interest in stromal expression of miR-21 in triple-negative breast cancer, for which prognostic markers and effective targeted therapies are lacking. 18 Van Andel Research Institute | Scientific Report

• Develop integrative diagnostics for pancreatic cancer and precursor lesions using information from studies of cancer-associated microRNAs and protein glycosylation. Integrating the data from both microRNAs and protein markers should enhance diagnostic power and interpretation. • Implement new technological platforms for high-content, tissue-based marker analysis. Our goal is a fully automated pipeline from tissue stain to image analysis that we can use to characterize tumor features and to study tumor compartment–specific events, such as molecular changes in cancer cells, paracrine signaling by tumor-associated fibroblasts, and anti-tumor immune cell responses. Molecular biology and cellular biology studies help to identify microRNA targets and regulatory networks. • Develop methods for isolating microRNA/target mRNA interactions in in vitro and in vivo systems. • In preclinical models and clinical specimens, identify tumor compartment–specific target networks that are regulated by microRNAs. • Evaluate tumor compartment–specific delivery of synthetic modulators of microRNA activity in preclinical cancer models and patient-derived cells. Genetic engineering of models lets us assess the role of microRNAs within tumor microenvironment compartments. • In animal models of breast and pancreatic cancers, evaluate the miR-21 activity required in cancer cell and tumor stroma compartments to support aggressive and metastatic features. • In preclinical models of pancreatic cancer, replenish miR-155 immunostimulatory activity in combination with immune checkpoint regulators to boost anti-tumor immunity. RECENT PUBLICATIONS Andrew, Angeline S., Carmen J. Marsit, Alan R. Schned, John D. Seigne, Karl T. Kelsey, Jason H. Moore, Laurent Perreard, Margaret R. Karagas, and Lorenzo F. Sempere. 2015. Expression of tumor suppressive microRNA-34a is associated with a reduced risk of bladder cancer recurrence. International Journal of Cancer 137(5): 1158–1166. Ensink, Elliot, Jessica Sinha, Arkadeep Sinha, Huiyuan Tang, Heather M. Calderone, Galen Hostetter, Jordan Winter, David Cherba, Randall E. Brand, et al. 2015. Segment and fit thresholding: a new method for image analysis applied to microarray and immunofluorescence data. Analytical Chemistry 87(19): 9715–9721. Graveel, Carrie R., Heather M. Calderone, Jennifer J. Westerhuis, Mary E. Winn, and Lorenzo F. Sempere. 2015. Critical analysis of the potential for microRNA biomarkers in breast cancer management. Breast Cancer: Targets and Therapy 7: 59–79. Machiela, Emily, Anthony Popkie, and Lorenzo F. Sempere. 2015. Individual noncoding RNA variations: their role in shaping and maintaining the epigenetic landscape. In Personalized Epigenetics, Trygve Tollefsbol, ed. Waltham, Massachusetts: Academic Press, pp. 84–122. CENTER FOR CANCER AND CELL BIOLOGY 19

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