title: Overexpression of MERTK receptor tyrosine kinase in epithelial cancer cells drives efferocytosis in a gain-of-function capacity.
abstract: MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in age-dependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKT-mediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggesting MERTK may preferentially interface with phosphatidylserine. Consistent with this idea, knockdown of MERTK in breast cancer cells MDA-MB 231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by soluble TAM receptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center.
authors: Khanh-Quynh N
authors: KQ
authors: Nguyen
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, Center for Immunity and Inflammation, New Jersey Medical School, and.
authors: Wen-I
authors: WI
authors: Tsou
authors: Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461.
authors: Daniel A
authors: DA
authors: Calarese
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center.
authors: Stanley G
authors: SG
authors: Kimani
authors: Department of Pathology and Laboratory Medicine, Flow Cytometry and Immunology Core Laboratory, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103.
authors: Sukhwinder
authors: S
authors: Singh
authors: Rutgers, New Jersey Medical School of Yeshiva University, Newark, New Jersey 07103.
authors: Shelly
authors: S
authors: Hsieh
authors: Institute of Biophysics and Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou 325035, China, and.
authors: Yongzhang
authors: Y
authors: Liu
authors: Institute of Biophysics and Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical University, Wenzhou 325035, China, and.
authors: Bin
authors: B
authors: Lu
authors: Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China.
authors: Yi
authors: Y
authors: Wu
authors: Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461.
authors: Scott J
authors: SJ
authors: Garforth
authors: Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461.
authors: Steve C
authors: SC
authors: Almo
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, Center for Immunity and Inflammation, New Jersey Medical School, and kotenkse@njms.rutgers.edu.
authors: Sergei V
authors: SV
authors: Kotenko
authors: From the Department of Biochemistry and Molecular Biology, University Hospital Cancer Center, birgera@njms.rutgers.edu.
authors: Raymond B
authors: RB
authors: Birge
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010587:Phagocytosis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; C084944:TYRO3 protein, human; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AXL; Apoptosis; Breast Cancer; Efferocytosis; Epithelial Cell; GAS6; MERTK; Phagocytosis; Protein S; Receptor-tyrosine Kinase