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Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets

Horman, Shane and To, Jeremy and Lamb, John and Zoll, Jocelyn and Leonetti, Nicole and Tu, Buu and Moran, Rita and Newlin, Robbin and Walker, John and Orth, Anthony (2017) Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets. Oncotarget, 8 (59). pp. 99913-99930. ISSN 19492553

Abstract

Recent advances in chemotherapeutics highlight the importance of molecularlytargeted perturbagens. Although these therapies typically address dysregulated cancer cell proteins, there are increasing therapeutic modalities that take into consideration cancer cell-extrinsic factors. Targeting components of tumor stroma such as vascular or immune cells has been shown to represent an efficacious approach in cancer treatment. Cancer-associated fibroblasts (CAFs) exemplify an important stromal component that can be exploited in targeted therapeutics, though their employment in drug discovery campaigns has been relatively minimal due to technical logistics in assaying for CAF-tumor interactions. Here we report a 3-dimensional multi-culture tumor:CAF spheroid phenotypic screening platform that can be applied to high-content drug discovery initiatives. Using a functional genomics approach we systematically profiled 1,024 candidate genes for CAF-intrinsic anti-spheroid activity; identifying several CAF genes important for development and maintenance of tumor:CAF coculture spheroids. Along with previously reported genes such as WNT, we identify CAF-derived targets such as ARAF and COL3A1 upon which the tumor compartment depends for spheroid development. Specifically, we highlight the G-protein-coupled receptor OGR1 as a unique CAF-specific protein that may represent an attractive drug target for treating colorectal cancer. In vivo, murine colon tumor implants in OGR1 knockout mice displayed delayed tumor growth compared to tumors implanted in wild type littermate controls. These findings demonstrate a robust microphysiological screening approach for identifying new CAF targets that may be applied to drug discovery efforts.

Item Type: Article
Keywords: 3D CAF GPR68 Screening Spheroid
Date Deposited: 19 Dec 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/32037

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