Cited by 108Prostate Cancer Treatment and ResearchProtease and Inhibitor MechanismsTGF-β signaling in diseases

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

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Nguyen, Elizabeth V., Pereira, Brooke A., Lawrence, Mitchell G., Ma, Xiuquan, Rebello, Richard J., Chan, Howard, Niranjan, Birunthi, Wu, Yunjian +9 more·2019·Molecular & Cellular Proteomics

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 cocultured 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.

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  • CAFs produce matrix-crosslinking enzymes and, together with force-mediated ECM remodelling, these contribute to increased stiffness of tumour tissue.

    “CAFs also produce matrix-crosslinking enzymes and, together with force-mediated ECM remodelling (reviewed in detail85,86), these contribute to the increased stiffness of tumour tissue87–89.”

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  1. [65]Bruderer R., Bernhardt O. M., Gandhi T., Miladinovic S. M., Cheng L. Y., Messner S., Ehrenberger T., Zanotelli V., Butscheid Y., Escher C., Vitek O., Rinner O., and Reiter L. (2015) Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol. Cell. Proteomics 14, 1400– 1410 25724911 PMC4424408
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Authors
Nguyen, E. V., Pereira, B. A., Lawrence, M. G., Ma, X., Rebello, R. J., Chan, H., Niranjan, B., Wu, Y., Ellem, S., Guan, X., Wu, J., Skhinas, J. N., Cox, T. R., Risbridger, G. P., Taylor, R. A., Lister, N. L., & Daly, R. J.
Affiliations
  • Peter MacCallum Cancer Centre (AU)
  • University of Southern Queensland (AU)
  • Peking University Cancer Hospital (CN)
  • Garvan Institute of Medical Research (AU)
  • The University of Melbourne (AU)
Corresponding author
Daly, Roger J.
Venue
Molecular & Cellular Proteomics
Publisher
Elsevier BV
Published
2019-07
Volume
18
Issue
7
Pages
1410-1427
ISSN
1535-9476 (ISSN-L)
OpenAlex
W2944168058
Cited by
107
References
98
Citations by year
2026: 12 · 2025: 16 · 2024: 15 · 2023: 17 · 2022: 10 · 2021: 17 · 2020: 19 · 2019: 1
FWCI
8.82
Type
journal article
Language
en
Open access
Locations
  • Molecular & Cellular Proteomics (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Southern Queensland ePrints (University of Southern Queensland) (acceptedVersion)
  • Monash University Research Portal (Monash University) (submittedVersion, other-oa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Cancer Australia (ID NCG2616)
  • Faculty of Medicine, Nursing and Health Sciences, Monash University (SGS16–0295)
  • Department of Health | National Health and Medical Research Council (NHMRC) (1102752, 1058540)
  • Victorian Cancer Agency (VCA) (15023)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
prostate cancer, cancer-associated fibroblasts, LOXL2, DDR2, tumor microenvironment, extracellular matrix, collagen cross-linking, phosphoproteome, proteomic profiling, intercellular communication, therapeutic target
MeSH terms
Cancer-Associated Fibroblasts, Amino Acid Oxidoreductases, Cell Movement, Epithelial Cells, Extracellular Matrix, Humans, Male, Neoplasm Proteins, Phosphoproteins, Phosphorylation, Prostate, Prostatic Neoplasms, Reproducibility of Results, Signal Transduction, Autocrine Communication, Paracrine Communication, Proteome, Proteomics, Cell Line, Tumor, Tumor Microenvironment

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