Melissa Wong is an Associate Professor in the Departments of Cell, Developmental, and Cancer Biology, Dermatology, , the Oregon Stem Cell Center, and is a member of the Knight Cancer Institute. She earned her Ph.D. degree in Molecular Pathobiology at Wake Forest University and trained with Dr. Jeffery Gordon at Washington University School of Medicine in St. Louis, MO. Dr. Wong came to OHSU in 2001.
My research program focuses on understanding the molecular mechanisms underlying stem cell regulation in the context of intestinal development, tissue regeneration, and disease. While stem cell biology is at the forefront of regenerative medicine, there lacks a clear understanding of the general mechanisms that regulate stem cell proliferation and ultimate lineage differentiation in tissue. This lack in knowledge hampers potential to harness stem cell biology for therapeutic purposes. The individual research projects in my laboratory encompass investigation of establishment of the regulatory stem cell niche during intestinal development, the dynamic remodeling of the intestinal stem cell niche during injury and disease, and the role of cellular fusion with intestinal stem cells in intestinal carcinogenesis.
The intestinal stem cell niche is defined by two discrete populations of stem cells, a rapidly cycling population defined by expression of the Wnt responsive gene Lgr5, and a slow-cycling population defined by expression of Bmi1. Recent studies suggest that the Bmi1-expressing population is not an active stem cell population, but rather a differentiating progenitor cell that is capable of dedifferentiating during stress environments to become an Lgr5-like stem cell. Our data counters this suggesting that Bmi1-expressing cells are the primary intestinal stem cell that drives tissue expansion during development of the intestine and is fundamental for tissue repair after injury. Our studies are focused on examining the two discrete states that Bmi1-expressing stem cells can exist in, and understanding the molecular mechanism by which state switch occurs.
Our laboratory has shown that circulating BMDCs fuse with intestinal stem cells upon tissue injury, inclusive of intestinal tumorigenesis. We now extend these studies to identify the cellular mediators of fusion, the underlying mechanism, and the long-term fate to the cell fusion hybrids. We have currently identified the macrophage population as a key bone marrow derived cell population in this fusion process. Our studies are now focused upon determine the fate of the cell fusion hybrids in participating to intestinal pathogenesis, as we examine genomic instability of the fusion hybrids, the ability of these cells to express macrophage genes under certain contexts, and the contribution of these cells to tumorigenesis. Our studies offer an exciting alternative view of how epithelia regenerate and have the potential to explain how chronic injury can lead to promote malignant tumors.
The cancer stem cell theory for why many cancers may recur after treatment presents a novel target for cancer therapeutics. However, the notion that cancer stem cells arise from mutations in tissue stem cells suggests that these two cell populations may share similar features and targetable epitopes. We have taken a systematic approach to defining surface antigens on these two populations by generating novel monoclonal antibodies. Our studies will establish a link between these two populations and may provide novel epitopes that are unique to the cancer stem cell that can be used for targeted therapy.
- Rizvi AZ, Swain JS, Bailey AS, Davies PS, Decker AD, Willenbring H, Grompe M, Fleming WH, and Wong MH. (2006) Bone marrow-derived cells fuse with normal and transformed intestinal progenitor cells. PNAS USA,103:6321-5.
- Powell AE, Davies PS, Anderson EA, Silk AD, Pelz C, Impey S and Wong MH. (2011) Fusion between Intestinal epithelial cells and Macrophages in a cancer context results in nuclear reprogramming. Cancer Res. 71:1497-1505. [PMCID: PMC3079548]
- Silk AD, Gast CE, Davies PS, Fakhari FD, Vanderbeek GE, Mori M, Wong MH. (2013) Fusion between hematopoietic and epithelial cells in adult human intestine. PLoS One. 8:e55572. [PMCID: PMC3559593]
Stem cell regulation
- Levin TG, Powell AE, Davies PS, Silk AD, Dismuke AD, Anderson EC, Swain JR, and Wong MH. (2010) Characterization of the intestinal cancer stem cell marker CD166 in the human and mouse gastrointestinal tract. Gastroenterology, 139:2072-2082. [PMCID: PMC2997177]
- Smith NR, Davies PS, Levin TG, Keene DR, Sengupta SK, El Rassi E, Wieghard N, Wong MH. (2017) CD166/ALCAM functions to orchestrate stem cell homeostasis within the niche. Cellular Molecular Gastro Hep. 3:387-409. [PMCID:PMC5404029]
- Yan KS, Janda CY, Chang J, Zheng GXY, Larkin KA, Luca VC, Chia LA, Mah AT, Han A, Terry JM, Ootani A, Roelf K, Lee M, Yuan J, Li X, Bolen CR, Wihlemy J, Davies P, Ueno H, von Furstenberg RJ, Belgrader P, Ziraldo SB, Ordonez H, Henning SJ, Wong MH, Snyder MP, Weissman IL, Hsueh AJ, Mikkelsen TS, Garcia KC, and Kuo CJ. Non-equivalence of Wnt and R-spondin ligands during Lgr5+intestinal stem cell renewal. (2017) Nature. 545:238-242. PMID 28467820
- Yan KS, Gevaert O, Zheng GXY, Anchang B, Probert CS, Larkin KA, Davies PS, Cheng Z, Kaddis JS, Han A, Roelf K, Calderon RI, Hu X, Wilhelmy J, Grimes S, Corney D, Boutet S, Terry JM, Belgrader P, Ziraldo SB, Mikkelsen TS, Wang F, von Furstenberg RJ, Smith NR, Chandrakesan P, May R, Chrissy M, Jain R, Cartwright CA, Niland JC, Hong Y, Carrington J, Breault D, Epstein J, Houchen CW, Lynch JP, Martin MG, Plevritis SK, Curtis C, Ji HP, Li L, Henning SJ, Wong MH, and Kuo CJ. Injury-inducible stem cell potential of the intestinal enterendocrine lineage. (2017) Cell Stem Cell. 21:78-90. PMID: 28686870