Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

Article


Nguyen, Elizabeth V., Pereira, Brooke A., Lawrence, Mitchell G., Ma, Xiuquan, Rebello, Richard J., Chan, Howard, Niranjan, Birunthi, Wu, Yunjian, Ellem, Stuart, Guan, Xiaoqing, Wu, Jianmin, Skhinas, Joanna N., Cox, Thomas R., Risbridger, Gail P., Taylor, Renea A., Lister, Natalie L. and Daly, Roger J.. 2019. "Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment." Molecular and Cellular Proteomics. 18 (7), pp. 1410-1427. https://doi.org/10.1074/mcp.RA119.001496
Article Title

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

ERA Journal ID2256
Article CategoryArticle
AuthorsNguyen, Elizabeth V. (Author), Pereira, Brooke A. (Author), Lawrence, Mitchell G. (Author), Ma, Xiuquan (Author), Rebello, Richard J. (Author), Chan, Howard (Author), Niranjan, Birunthi (Author), Wu, Yunjian (Author), Ellem, Stuart (Author), Guan, Xiaoqing (Author), Wu, Jianmin (Author), Skhinas, Joanna N. (Author), Cox, Thomas R. (Author), Risbridger, Gail P. (Author), Taylor, Renea A. (Author), Lister, Natalie L. (Author) and Daly, Roger J. (Author)
Journal TitleMolecular and Cellular Proteomics
Journal Citation18 (7), pp. 1410-1427
Number of Pages18
Year2019
Place of PublicationUnited States
ISSN1535-9476
1535-9484
Digital Object Identifier (DOI)https://doi.org/10.1074/mcp.RA119.001496
Web Address (URL)https://www.sciencedirect.com/science/article/pii/S1535947620315486
Abstract

In prostate cancer, cancer-associated fibroblasts (CAF) exhibit contrasting biological properties to non-malignant prostate fibroblasts (NPF) and promote tumorigenesis. Resolving intercellular signaling pathways between CAF and prostate tumor epithelium may offer novel opportunities for research translation. To this end, the proteome and phosphoproteome of four pairs of patient-matched CAF and NPF were characterized to identify discriminating proteomic signatures. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with a hyper reaction monitoring data-independent acquisition (HRM-DIA) workflow. Proteins that exhibited a significant increase in CAF versus NPF were enriched for the functional categories “cell adhesion” and the “extracellular matrix.” The CAF phosphoproteome exhibited enhanced phosphorylation of proteins associated with the “spliceosome” and “actin binding.” STRING analysis of the CAF proteome revealed a prominent interaction hub associated with collagen synthesis, modification, and signaling. It contained multiple collagens, including the fibrillar types COL1A1/2 and COL5A1; the receptor tyrosine kinase discoidin domain-containing receptor 2 (DDR2), a receptor for fibrillar collagens; and lysyl oxidase-like 2 (LOXL2), an enzyme that promotes collagen crosslinking. Increased activity and/or expression of LOXL2 and DDR2 in CAF were confirmed by enzymatic assays and Western blotting analyses. Pharmacological inhibition of CAF-derived LOXL2 perturbed extracellular matrix (ECM) organization and decreased CAF migration in a wound healing assay. Further, it significantly impaired the motility of co-cultured RWPE-2 prostate tumor epithelial cells. These results indicate that CAF-derived LOXL2 is an important mediator of intercellular communication within the prostate tumor microenvironment and is a potential therapeutic target.

KeywordsPhosphoproteome; Prostate cancer; Prostate cancer biomarkers; Tumor microenvironment; Cancer biomarker(s); Cancer-associated fibroblasts; Fibroblasts; LOXL2; Non-malignant prostate fibroblasts
Contains Sensitive ContentDoes not contain sensitive content
ANZSRC Field of Research 2020321101. Cancer cell biology
320214. Nephrology and urology
321199. Oncology and carcinogenesis not elsewhere classified
Institution of OriginUniversity of Southern Queensland
Byline AffiliationsMonash University
Victorian Comprehensive Cancer Centre, Australia
School of Health and Wellbeing
Peking University Cancer Hospital and Institute, China
Garvan Institute of Medical Research, Australia
University of Melbourne
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