Serk In Park, D.D.S, Ph.D.
Assistant Professor of Medicine (Clinical Pharmacology)
Assistant Professor of Cancer Biology
Vanderbilt University Medical Center
1225E MRB IV
Nashville, TN 37232
The primary goal of my laboratory aims to address what makes bone the most favored organ of prostate cancer spreading. Advanced-stage prostate cancer patients uniformly develop bone lesions (i.e. bone metastasis), resulting in severe pain, immobility, and ultimately death. A major hurdle to develop means of preventing or curing bone metastasis stems from the diversity of cell types constituting bone and the bone marrow, and determining how these cells may be involved. Indeed, the bone marrow is a reservoir of blood-forming cells, and also serves as a seedbed for the cancer cells spreading to bone. My laboratory endeavors to understand how exactly the bone marrow cells contribute to the development of bone metastasis, and ultimately how to suppress those cells to treat bone metastasis. Research outcomes from my laboratory will have impacts on understanding how prostate cancer exploits the bone marrow cells to colonize bone, and more importantly will help provide biological rationale and means for targeting a specific cell type in the bone marrow as a therapeutic approach for prostate cancer patients.
- D.D.S, Yonsei University, Seoul, Korea
- Ph.D. in Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
- Research Fellowship, The University of Michigan, Ann Arbor, MI
Bone marrow-derived cells in the prostate cancer microenvironment
The tumor microenvironment is comprised of primary cancer cells mixed with multiple types of stromal cells, of which a significant fraction originates in the bone marrow. For this reason, bone is an essential partner for tumor progression. However, it is unclear how tumor cells co-opt the bone and/or bone marrow to facilitate a favorable tumor microenvironment.
Among those bone marrow-derived cells in the tumor microenvironment, a subset of myeloid lineage cells, myeloid-derived suppressor cells (MDSCs), has been shown to correlate significantly with tumor progression. MDSCs suppress the host immune response and infiltrate tumor tissue to promote tumor growth and angiogenesis. Beyond these critical roles, little is known about the regulation of MDSCs within bone by distant primary tumor cells, not to mention therapeutic approaches targeting MDSCs.
The Park Laboratory aims to address how tumor cells stimulate the bone microenvironment to regulate MDSCs, contributing to tumor growth, angiogenesis and/or metastasis.
For this aim, prostate cancer takes a unique position, not only because of disastrous mortality and morbidity, but also because of preferential metastasis to the skeleton. Accordingly, prostate cancer cells secrete numerous important bone-modulating cytokines, leading to osteoblastic/osteolytic reactions that stimulate the adjacent bone marrow cells.
We will investigate the molecular mechanism of MDSC activation, expansion, and/or mobilization within the bone marrow of prostate tumor hosts. Additionally, we will examine the therapeutic approaches targeting MDSCs in pre-clinical models with investigational drugs. The potential research outcomes will promote understanding of the vicious partnership between cancer and bone.
- Cho, SW, Soki, FN, Koh, AJ, Eber, MR, Entezami, P, Park, SI, van Rooijen, N, McCauley, LK Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone. Proc Natl Acad Sci U S A, 111(4), 1545-50, 2014.
- Jin, R, Sterling, JA, Edwards, JR, DeGraff, DJ, Lee, C, Park, SI, Matusik, RJ Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PLoS One, 8(4), e60983, 2013.
- Park, SI, Lee, C, Sadler, WD, Koh, AJ, Jones, J, Seo, JW, Soki, FN, Cho, SW, Daignault, SD, McCauley, LK Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth. Cancer Res, 73(22), 6574-83, 2013.
- Zhang, H, Yu, C, Dai, J, Keller, JM, Hua, A, Sottnik, JL, Shelley, G, Hall, CL, Park, SI, Yao, Z, Zhang, J, McCauley, LK, Keller, ET Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of ¿¿-catenin activation of the DKK1 promoter in prostate cancer. Oncogene, 2013.
- Ding, X, Park, SI, McCauley, LK, Wang, CY Signaling between transforming growth factor ¿¿ (TGF-¿¿) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis. J Biol Chem, 288(15), 10241-53, 2013.
- Park, SI, Liao, J, Berry, JE, Li, X, Koh, AJ, Michalski, ME, Eber, MR, Soki, FN, Sadler, D, Sud, S, Tisdelle, S, Daignault, SD, Nemeth, JA, Snyder, LA, Wronski, TJ, Pienta, KJ, McCauley, LK Cyclophosphamide creates a receptive microenvironment for prostate cancer skeletal metastasis. Cancer Res, 72(10), 2522-32, 2012.
- Park, SI, McCauley, LK Nuclear localization of parathyroid hormone-related peptide confers resistance to anoikis in prostate cancer cells. Endocr Relat Cancer, 19(3), 243-54, 2012.
- Jung, Y, Shiozawa, Y, Wang, J, McGregor, N, Dai, J, Park, SI, Berry, JE, Havens, AM, Joseph, J, Kim, JK, Patel, L, Carmeliet, P, Daignault, S, Keller, ET, McCauley, LK, Pienta, KJ, Taichman, RS Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment. Neoplasia, 14(5), 429-39, 2012.
- Soki, FN, Park, SI, McCauley, LK The multifaceted actions of PTHrP in skeletal metastasis. Future Oncol, 8(7), 803-17, 2012.
- Li, X, Liao, J, Park, SI, Koh, AJ, Sadler, WD, Pienta, KJ, Rosol, TJ, McCauley, LK Drugs which inhibit osteoclast function suppress tumor growth through calcium reduction in bone. Bone, 48(6), 1354-61, 2011.
- Li, X, Koh, AJ, Wang, Z, Soki, FN, Park, SI, Pienta, KJ, McCauley, LK Inhibitory effects of megakaryocytic cells in prostate cancer skeletal metastasis. J Bone Miner Res, 26(1), 125-34, 2011.
- Park, SI, Soki, FN, McCauley, LK Roles of bone marrow cells in skeletal metastases: no longer bystanders. Cancer Microenviron, 4(3), 237-46, 2011.
- Park, SI, Kim, SJ, McCauley, LK, Gallick, GE Pre-clinical mouse models of human prostate cancer and their utility in drug discovery. Curr Protoc Pharmacol, Chapter 14Unit 14.15, 2010.
- Kopetz, S, Lesslie, DP, Dallas, NA, Park, SI, Johnson, M, Parikh, NU, Kim, MP, Abbruzzese, JL, Ellis, LM, Chandra, J, Gallick, GE Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res, 69(9), 3842-9, 2009.
- Park, SI, Zhang, J, Phillips, KA, Araujo, JC, Najjar, AM, Volgin, AY, Gelovani, JG, Kim, SJ, Wang, Z, Gallick, GE Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res, 68(9), 3323-33, 2008.
- Zhang, J, Park, SI, Artime, MC, Summy, JM, Shah, AN, Bomser, JA, Dorfleutner, A, Flynn, DC, Gallick, GE AFAP-110 is overexpressed in prostate cancer and contributes to tumorigenic growth by regulating focal contacts. J Clin Invest, 117(10), 2962-73, 2007.
- Shah, AN, Summy, JM, Zhang, J, Park, SI, Parikh, NU, Gallick, GE Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol, 14(12), 3629-37, 2007.
- Park, SI, Shah, AN, Zhang, J, Gallick, GE Regulation of angiogenesis and vascular permeability by Src family kinases: opportunities for therapeutic treatment of solid tumors. Expert Opin Ther Targets, 11(9), 1207-17, 2007.