MerTK Drives Proliferation and Metastatic Potential in Triple-Negative Breast Cancer

Author:

Iida Mari1ORCID,Crossman Bridget E.1ORCID,Kostecki Kourtney L.1ORCID,Glitchev Christine E.1,Kranjac Carlene A.1,Crow Madisen T.1,Adams Jillian M.1,Liu Peng23,Ong Irene234,Yang David T.5ORCID,Kang Irene6,Salgia Ravi6ORCID,Wheeler Deric L.13

Affiliation:

1. Department of Human Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA

2. Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53726, USA

3. Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA

4. Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, WI 53705, USA

5. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA

6. Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA

Abstract

Triple-negative breast cancer (TNBC) is characterized by the absence of the estrogen receptor, progesterone receptor, and receptor tyrosine kinase HER2 expression. Due to the limited number of FDA-approved targeted therapies for TNBC, there is an ongoing need to understand the molecular underpinnings of TNBC for the development of novel combinatorial treatment strategies. This study evaluated the role of the MerTK receptor tyrosine kinase on proliferation and invasion/metastatic potential in TNBC. Immunohistochemical analysis demonstrated MerTK expression in 58% of patient-derived TNBC xenografts. The stable overexpression of MerTK in human TNBC cell lines induced an increase in proliferation rates, robust in vivo tumor growth, heightened migration/invasion potential, and enhanced lung metastases. NanoString nCounter analysis of MerTK-overexpressing SUM102 cells (SUM102-MerTK) revealed upregulation of several signaling pathways, which ultimately drive cell cycle progression, reduce apoptosis, and enhance cell survival. Proteomic profiling indicated increased endoglin (ENG) production in SUM102-MerTK clones, suggesting that MerTK creates a conducive environment for increased proliferative and metastatic activity via elevated ENG expression. To determine ENG’s role in increasing proliferation and/or metastatic potential, we knocked out ENG in a SUM102-MerTK clone with CRISPR technology. Although this ENG knockout clone exhibited similar in vivo growth to the parental SUM102-MerTK clone, lung metastasis numbers were significantly decreased ~4-fold, indicating that MerTK enhances invasion and metastasis through ENG. Our data suggest that MerTK regulates a unique proliferative signature in TNBC, promoting robust tumor growth and increased metastatic potential through ENG upregulation. Targeting MerTK and ENG simultaneously may provide a novel therapeutic approach for TNBC patients.

Funder

University of Wisconsin Carbone Cancer Center (UWCCC) Breast DOT

NIH/NCI

Office of the Director—NIH

Publisher

MDPI AG

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. MERTK Inhibition as a Targeted Novel Cancer Therapy;International Journal of Molecular Sciences;2024-07-12

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