Therapeutic Targeting of Stromal-Tumor HGF-MET Signaling in an Organotypic Triple-Negative Breast Tumor Model.

Autor:	Singh S; Department of Biomedical Engineering, The University of Akron, Akron, Ohio., Lamichhane A; Department of Biomedical Engineering, The University of Akron, Akron, Ohio., Rafsanjani Nejad P; Department of Biomedical Engineering, The University of Akron, Akron, Ohio., Heiss J; Department of Biomedical Engineering, The University of Akron, Akron, Ohio., Baumann H; Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio., Gudneppanavar R; Department of Chemistry, The University of Akron, Akron, Ohio., Leipzig ND; Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Akron, Ohio., Konopka M; Department of Chemistry, The University of Akron, Akron, Ohio., Luker GD; Departments of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, Michigan., Tavana H; Department of Biomedical Engineering, The University of Akron, Akron, Ohio.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2022 Jul 06; Vol. 20 (7), pp. 1166-1177.
DOI:	10.1158/1541-7786.MCR-21-0317
Abstrakt:	The tumor microenvironment (TME) promotes proliferation, drug resistance, and invasiveness of cancer cells. Therapeutic targeting of the TME is an attractive strategy to improve outcomes for patients, particularly in aggressive cancers such as triple-negative breast cancer (TNBC) that have a rich stroma and limited targeted therapies. However, lack of preclinical human tumor models for mechanistic understanding of tumor-stromal interactions has been an impediment to identify effective treatments against the TME. To address this need, we developed a three-dimensional organotypic tumor model to study interactions of patient-derived cancer-associated fibroblasts (CAF) with TNBC cells and explore potential therapy targets. We found that CAFs predominantly secreted hepatocyte growth factor (HGF) and activated MET receptor tyrosine kinase in TNBC cells. This tumor-stromal interaction promoted invasiveness, epithelial-to-mesenchymal transition, and activities of multiple oncogenic pathways in TNBC cells. Importantly, we established that TNBC cells become resistant to monotherapy and demonstrated a design-driven approach to select drug combinations that effectively inhibit prometastatic functions of TNBC cells. Our study also showed that HGF from lung fibroblasts promotes colony formation by TNBC cells, suggesting that blocking HGF-MET signaling potentially could target both primary TNBC tumorigenesis and lung metastasis. Overall, we established the utility of our organotypic tumor model to identify and therapeutically target specific mechanisms of tumor-stromal interactions in TNBC toward the goal of developing targeted therapies against the TME. Implications: Leveraging a state-of-the-art organotypic tumor model, we demonstrated that CAFs-mediated HGF-MET signaling drive tumorigenic activities in TNBC and presents a therapeutic target. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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