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2013 Scientific Report

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Matthew Steensma, M.D.

Matthew Steensma, M.D. Laboratory of Musculoskeletal Oncology Dr. Steensma received his BA from Hope College and his M.D. from Wayne State University School of Medicine in Detroit. He was admitted into the fellowship program in musculoskeletal surgical oncology at Memorial Sloan-Kettering Cancer Center in New York, obtaining subspecialty training in surgical management of musculoskeletal tumors. Upon completion of this training, Dr. Steensma worked in the laboratory of Dr. Steve Goldring, one of the world’s leading orthopaedic researchers. There Dr. Steensma further developed his interest in understanding the molecular and cellular mechanisms underlying bone and soft-tissue sarcomas. Dr. Steensma is a practicing physician, treating patients in his musculoskeletal oncology clinic, and he joined VARI in 2010 as an Assistant Professor. From left: Steensma, Scholten, Kampfshulte, Ringler, Peacock, Pelle Staff Diana Lewis, A.S. Jacqueline Peacock, Ph.D. Jonathan Ringler, M.S. Students Kevin Kampfshulte, B.A. D.J. Scholten, B.A. Visiting Scientist Dominic Pelle, M.D. 49

Van Andel Research Institute | Scientific Report Research Interests Our laboratory is particularly interested in defining the mechanisms of tumor initiation and disease progression for a rare type of cancer called sarcoma. In doing so, we seek to identify novel diagnostic and therapeutic targets for the disease. The lab centers its efforts around two disease entities: the primary bone cancer, called osteosarcoma, and Type 1 neurofibromatosis (NF1), also called Von Recklinghausen’s disease. Osteosarcoma affects predominantly children and young adults; it arises directly from bone and is highly aggressive. Advances in treatment have been slow over the last four decades, particularly with respect to metastatic osteosarcoma, which is largely incurable. Our lab is studying mechanisms whereby certain cells within the primary tumor resist chemotherapy, spread to a distant site, and reinitiate tumor formation (i.e., the process of metastasis). This subpopulation resembles mesenchymal stem cells in that they are capable of continuous self-renewal and multipotent differentiation. As a group, these cells are often referred to as tumor-initiating cells. The role of the microenvironment in the formation of these cells within the primary tumor and metastatic lesions is poorly understood. We are examining the effect of up-regulated hypoxia-inducible factor (HIF) signaling on tumor-initiating cell formation to determine whether HIF antagonists are useful adjuncts in preventing latent recurrence of osteosarcoma. We are also conducting genomic profiling studies of osteosarcomas to identify novel biomarkers and drug targets. This work is in collaboration with Drs. Craig Webb and Giselle Scholler. By comparing gene expression and mutational profiles of tumor-initiating cells with those of the bulk tumor, we aim to identify novel therapeutic targets specific to the most treatment-resistant cell populations. NF1 is an inherited disease that predisposes the affected individuals to both benign and malignant tumors. The lifetime incidence of sarcoma development in NF1 is about 10%, which is nearly 10,000-fold higher than for non-affected individuals. NF1-related sarcomas are highly aggressive and do not respond well to chemotherapy. Individuals with NF1 carry a mutation in one of two copies of the gene encoding neurofibromin (NF1), which results in deregulated RAS signaling. Loss of the second copy of NF1 is necessary for cancer to develop, but other factors have also been shown to be important for malignant transformation. Specifically, the lab is examining how HGF/MET signal activation drives both neurofibroma and neurofibrosarcoma development in the context of NF1. This work is being accomplished using novel, genetically engineered mouse models. Through a collaboration with Craig Webb, we are also applying a systems biology approach for analyzing clinical samples in anticipation of an NF1 personalized medicine trial. Recent Publications Steensma, Matthew, and John H. Healey. In press. Trends in the surgical treatment of pathologic proximal femur fractures among Musculoskeletal Tumor Society members. Clinical Orthopaedics and Related Research. Steensma, M.R., and C. Morris. In press. Ewing’s sarcoma. In Orthopaedic Knowledge Update, S. Biermann, ed. Rosemont, IL: American Academy of Orthopaedic Surgeons. Valkenburg, Kenneth C., Matthew R. Steensma, Bart O. Williams, and Zhendong Zhong. In press. Skeletal metastasis: treatments, mouse models, and Wnt signaling. Chinese Journal of Cancer. Zhong, Zhendong, Bart O. Williams, and Matthew R. Steensma. 2012. The activation of b-catenin by Gas contributes to the etiology of phenotypes seen in fibrous dysplasia and McCune-Albright syndrome. IBMS BoneKEy 9: 113. 50

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