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2018 Scientific Report

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Center for Cancer and

Center for Cancer and Cell Biology 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 Josh Schipper, Ph.D. Jeanie Wedberg, A.S. Jenni Westerhuis, M.S.Ed., M.S. STUDENTS Sudakshina Chakrabarty Joyce Goodluck 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 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 small-molecule inhibitors. The laboratory has active projects in the areas of cancer biology and tumor microenvironment, with a translational focus toward improving diagnostic applications and therapeutic strategies. Because tissue samples are the direct connection between cancer research and cancer medicine, detailed molecular and cellular characterization of tumors provides the opportunity to translate scientific knowledge into useful clinical information. We use innovative multiplexed immunohistochemical and in situ hybridization assays to implement diagnostic applications of microRNA biomarkers. Molecular biology and cell biology studies help to identify microRNA targets and regulatory networks. Recent projects include the following. • Clinically validating tumor compartment-specific expression of miR-21 as a prognostic marker for breast cancer. There is focused interest in the stromal expression of miR-21 in triple-negative breast cancer, for which prognostic markers and effective targeted therapies are lacking. • Developing integrative diagnostics for pancreatic cancer using information from cancer-associated microRNAs and protein glycosylation. Integrative marker analysis should enhance diagnostic power and interpretation. • Developing methods for isolating microRNA/target mRNA interactions in in vitro and in vivo systems. • Evaluating the miR-21 activity required in cancer cell and tumor stromal compartments to support aggressive and metastatic features in animal models of breast and pancreatic cancer. 12 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

MATTHEW STEENSMA, M.D. Dr. Steensma received his B.A. from Hope College and his M.D. from Wayne State University School of Medicine in Detroit. He is a practicing surgeon in the Spectrum Health Medical Group, and he joined VARI as an Assistant Professor in 2010. STAFF Patrick Dischinger, B.S., MB(ASCP) CM Curt Essenburg, B.S., LATG Carrie Graveel, Ph.D. Michelle Minard, B.S. Elizabeth Tovar, Ph.D. RESEARCH INTERESTS Our laboratory conducts research into new treatment strategies for sarcomas. Specifically, we are interested in determining the mechanisms underlying tumor formation in sporadic bone and soft-tissue sarcomas and in neurofibromatosis type 1, a hereditary disorder caused by mutations in the neurofibromin 1 (NF1) gene. Neurofibromin is considered a tumor suppressor that suppresses Ras activity by promoting Ras GTP hydrolysis to GDP. People with mutations in the NF1 gene develop benign tumors called neurofibromas and have an elevated risk of malignancies ranging from solid tumors (including sarcomas) to leukemia. The disease affects 1 in 3000 people in the United States, of whom 8–13% will ultimately develop a neurofibromatosis-related sarcoma in their lifetime. These aggressive tumors typically arise from benign neurofibromas, but the process of benign-tomalignant transformation is not well understood, and treatment options are limited, leading to poor five-year survival rates. Our current research efforts include the development of genetically engineered mouse models of neurofibromatosis type 1 tumor progression, most notably NF1- related MPNSTs and breast cancer; the identification of targetable patterns of intratumoral and intertumoral heterogeneity through next-generation sequencing; genotype–phenotype correlations in neurofibromatosis type 1 and related diseases; and mechanisms of chemotherapy resistance in bone and soft-tissue sarcomas. STUDENTS Eve Gardner Jamie Grit, B.S. Candace King, M.A. Courtney Schmidt VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 13

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