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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Lorenzo F. Sempere, Ph.D. Laboratory of microRNA Diagnostics and Therapeutics Dr. Sempere obtained his B.S. in biochemistry at Universidad Miguel Hernández, Elche, Spain. He trained in the laboratory of Victor Ambros at Dartmouth College and is currently an Assistant Professor in the Center for Cancer and Cell Biology. He has expertise in diverse areas of microRNA research, including evolutionary and developmental biology, molecular and cellular biology, and immunology and cancer biology. He is the editor of the journal microRNA Diagnostics and Therapeutics. From left: Westerhuis, Calderone, Grit, Weaver, Sempere Staff Heather Calderone, Ph.D. Jamie Grit, B.S. Laura Weaver Jenni Westerhuis, M.S.Ed., M.S. 28

Sempere 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 mRNA expression of hundreds of target genes, some of which are components of the same signaling pathways or biological processes. Accordingly, 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 small-molecule 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. Knowledge of microRNAs is integrated into collaborative efforts with VARI researchers and cores, as well as into new technologies being developed for microRNA studies. Work in the laboratory includes the following. • Molecular pathology with innovative human tissue–based multiplex ISH/IHC assays to implement diagnostic applications of microRNA biomarkers in a clinical setting. Tissue samples are the direct connection between cancer research and cancer medicine. Detailed cellular and molecular characterization of tumors presents a unique opportunity to translate scientific knowledge into useful clinical information. – Clinically validate tumor compartment–specific expression of miR-21 as a novel prognostic marker in breast cancer. There is a focused interest in stromal expression of miR-21 for risk assessment and stratification of patients with triple-negative breast cancer, for which prognostic markers and effective targeted therapies are lacking. – Develop integrative diagnostic applications for pancreatic cancer and precursor lesions using information derived from cancer-associated microRNAs and glycosylation biology. Integration of informative microRNA and protein markers should enhance diagnostic power and interpretation. – Implement innovative 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 interrogate the biology of tumor compartment–specific events such as molecular alterations in cancer cells, paracrine signaling by tumor-associated fibroblasts, and anti-tumor immune cell responses. • Genetic engineering of models to assess the role of microRNAs within tumor microenvironment compartments. – Evaluate the miR-21 activity required in cancer cell and tumor stroma compartment(s) to support aggressive and metastatic features in animal models of breast and pancreatic cancers. – Replenish miR-155 immunostimulatory activity in combination with immune checkpoint regulators to boost antitumor immunity in preclinical models of pancreatic cancer. • Molecular biology and cellular biology studies to identify microRNA targets and regulatory networks. – Develop methods for isolating microRNA/target mRNA interactions in in vitro and in vivo systems. – Identify tumor compartment–specific microRNA-regulated target networks in preclinical models and clinical specimens. – Evaluate tumor compartment–specific delivery of synthetic microRNA activity modulators in preclinical cancer models and patient-derived cells (e.g., cancer cells, tumor-associated fibroblasts, dendritic cells). Recent Publications Mackenzie, T.A., G.N. Schwartz, H.M. Calderone, C.R. Graveel, M.E. Winn, G.Hostetter, W.A. Wells, and L.F. Sempere. In press. Stromal expression of miR-21 identifies high-risk group in triple-negative breast cancer. American Journal of Pathology. Sempere, Lorenzo F. 2014. Tissue slide-based microRNA characterization of tumors: how detailed could diagnosis become for cancer medicine? Expert Review of Molecular Diagnostics 14(7): 853–869. 29

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