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"Overexpression of MER Receptor Tyrosine Kinase in Epithelial Cancer Cells Drives Efferocytosis in a Gain-of-Function Capacity"

Khanh Quynh Ngoc Nguyen
Biochemistry and Molecular Biology Program
B.S. 2007, Montclair State University

Thesis Advisor: Raymond B. Birge, Ph.D.
Department of Biochemistry and Molecular Biology

Monday, June 16, 2014
2:00 P.M., MSB E-609b


MER, a member of the TAM (TYRO3, AXL, and MER) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knockout of MER results in age-dependent autoimmunity characterized by a failure to apoptotic clearance, while on the other, MER over-expression in cancer drives classical oncogenic signaling pathways such as PI3-kinase and ERK leading to cell transformation. To better understand the interplay between transformation and efferocytosis, we stably expressed MER in human MCF10A cells, an immortalized breast epithelial cell line devoid of endogenous Mer. Stable expression of MER in MCF10A cells resulted in the surface expression of partially active receptor, which could be fully activated by addition of exogenous ligand GAS6. While MCF10A-MER stable cells showed enhanced motility towards both serum and GAS6, these cells did not form stable colonies in soft agar, nor did MER expression drive enhanced proliferation compared to parental MCF10A cells. However, when treated with camptothecin, MCF10A-MER cells were protected from chemotherapy-induced apoptosis, and concomitantly activated AKT. Concomitant to the suppression of apoptosis, MER also stimulated efferocytosis in a potent gain-of-function capacity in epithelial cells. Moreover, while AXL activation was maximized by native ligand GAS6 and independent of apoptotic cells, the activation of MER was highly dependent on apoptotic cells, suggesting MER may preferentially interface with phosphatidylserine. Indeed, consistent with the idea that MER acts as a stand-alone receptor for efferocytosis, primary mammary epithelial cells isolated from MER(-/-) mice showed diminished efferocytosis, while forced transient expression of MER stimulated efferocytosis in all cell lines tested including MCF10A, Hela, and primary mouse epithelial 21 cells. Finally, human breast cancer cell lines that had high endogenous MER showed higher constitutive levels of efferocytosis, which could be blocked by TAM soluble receptor traps. These data collectively identify MER as a significant link between cancer and efferocytosis, and a potentially new and unrealized oncogenic event when MER is overexpressed in epithelial cells. Our findings provide new mechanistic insight into how MER functions as an oncogene in epithelial transformed cells.

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