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2016 Scientific Report

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XIAOHONG LI, PH.D. Dr. Li received her Ph.D. from the Institute of Zoology, Chinese Academy of Sciences, in Beijing in 2001. She joined VARI as an Assistant Professor in September 2012. STAFF PAUL G. DAFT, PH.D. SOURIK GANGULY, PH.D. DIANA LEWIS, A.S. NEIL (XIANGQI) MENG, PH.D. ALEXANDRA VANDER ARK, M.S. JIE WANG, M.D. QI ZENG, M.D. RESEARCH INTERESTS Our laboratory is committed to understanding tumor dormancy and cancer bone metastases, specifically of breast, lung, and prostate cancers. Our long-term goal is to create a dormancy-permissive bone microenvironment so that cancer cells can be kept dormant or be killed while they are in that state. Project 1. Cell-specific roles of transforming growth factor (TGF)-β in bone metastases. STUDENTS AUSTIN M. MEADOWS GHADA Y.T. MOHSEN ERICA WOODFORD Most people who die of cancer have metastases somewhere in their body, but metastases of certain cancers, particularly of the breast, lung, or prostate, are more likely to be found in bone. Cancer cells in bone induce either osteolytic (bone resorption) or osteoblastic (abnormal bone formation) lesions, which can cause fractures, spinal cord compression, hypercalcemia, and extreme bone pain. Current treatments for bone-metastasis patients can reduce symptoms such as pain but do not increase survival. Better understanding of the mechanism of bone metastasis is needed in order to develop early diagnostic tests and targeted therapeutic strategies. The local events of bone lesion development are determined by the interactions of cancer cells with bone cells such as osteoblasts (mesenchymal lineage) and osteoclasts (myeloid lineage), and such events are regulated by growth factors and cytokines of the bone matrix. The cytokine TGF-β plays crucial roles in both cancerous and healthy bone, and its effects are highly context-dependent, spatially and temporally. We aim to delineate the cell-specific role of TGF-β in bone metastasis and identify downstream mediators that can be targeted by new therapies. 12 Van Andel Research Institute | Scientific Report

Our studies have produced the following results. • Basic fibroblast growth factor (bFGF), mediated by TGF-β signaling in cells of the myeloid lineage, promotes breast cancer bone metastasis. By blocking bFGF, we can reduce such bone lesion development. In bone metastatic tissues from breast cancer patients, TGF-β and bFGF signaling are likely to be activated in osteoclasts and cancer cells but inactivated in osteoblasts. • TGF-β signaling in myeloid lineage cells promotes bone metastasis, but in cells of the mesenchymal lineage, the same signaling inhibits bone metastasis. We have found that bFGF is the functional mediator for TGF-β signaling effects only in cells of the myeloid lineage. Project 2. TGF-β signaling in the bone microenvironment affects tumor dormancy. Up to 70% of cancer patients have tumor cells in the bone marrow at the time of initial diagnosis. It is not known how cancer cells in bone remain dormant and later reactivate. Understanding tumor dormancy is important in trying to prevent the metastatic recurrences that kill patients. Studies have shown that external cues from the bone microenvironment can determine tumor cell dormancy. We aim to create a dormancy-permissive bone microenvironment and determine the mechanism by which it supports cancer cell dormancy. We have established a system in which loss of TGF-β signaling in myeloid lineage cells may promote the dormancy of prostate cancer or NSCLC in the bone marrow. We are now studying the underlying mechanism. • The cell-specific roles of TGF-β signaling are more complex for bone metastasis of non-small-cell lung cancer (NSCLC). The effects are dependent on the types of bone lesions that are produced by different NSCLC tumors. RECENT PUBLICATIONS Meng, X., A. Vander Ark, P. Lee, G. Hostetter, N.A. Bhowmick, L.M. Matrisian, B.O. Williams, C.K. Miranti, and X. Li. 2016. Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis. Oncogene 35(18): 2370-2378. CENTER FOR CANCER AND CELL BIOLOGY 13

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