Proteomics

Dataset Information

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Proteomic profiling of human prostate cancer-associated fibroblasts identifies LOXL2 promotes tumour migration in the extracellular matrix


ABSTRACT: In prostate cancer (PC), cancer-associated fibroblasts (CAFs) exhibit contrasting biological properties to non-malignant prostate fibroblasts (NPFs) and promote tumorigenesis. Resolving intercellular signaling pathways between CAFs and prostate tumor epithelium may offer novel opportunities for research translation. To this end, the proteome and phosphoproteome of four pairs of patient-matched CAFs and NPFs 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 CAFs versus NPFs 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), which promotes collagen crosslinking. Increased activity and/or expression of LOXL2 and DDR2 in CAFs were confirmed by enzymatic assays and Western blot analyses. Pharmacological inhibition of CAF-derived LOXL2 perturbed extracellular matrix (ECM) organization and decreased cell migration in wound-healing assays. Furthermore, it significantly impaired the motility of co-cultured RWPE2 prostate tumor epithelial cells. These results indicate that CAF-derived LOXL2 is an important mediator of intercellular communication within the PC tumor microenvironment and a potential therapeutic target.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Elizabeth Nguyen  

LAB HEAD: Roger Daly

PROVIDER: PXD010611 | Pride | 2019-05-24

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20160204_CAF_105_1_DDA.index Other
20160204_CAF_105_1_DDA.raw Raw
20160204_CAF_105_2_DDA.index Other
20160204_CAF_105_2_DDA.raw Raw
20160204_CAF_105_3_DDA.index Other
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Publications

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

Nguyen Elizabeth V EV   Pereira Brooke A BA   Lawrence Mitchell G MG   Ma Xiuquan X   Rebello Richard J RJ   Chan Howard H   Niranjan Birunthi B   Wu Yunjian Y   Ellem Stuart S   Guan Xiaoqing X   Wu Jianmin J   Skhinas Joanna N JN   Cox Thomas R TR   Risbridger Gail P GP   Taylor Renea A RA   Lister Natalie L NL   Daly Roger J RJ  

Molecular & cellular proteomics : MCP 20190506 7


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  ...[more]

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