CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation

Fibroblast activation is associated with tumor progression and implicated in metastasis, but the initial triggering signals required to kick-start this process remain largely unknown. Because small cancerous lesions share limited physical contact with neighboring fibroblasts, we reasoned the first t...

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Bibliographic Details
Published in:Molecular & cellular proteomics Vol. 17; no. 8; p. 1502
Main Authors: Wu, Wei, Zaal, Esther A, Berkers, Celia R, Lemeer, Simone, Heck, Albert J R
Format: Journal Article
Language:English
Published: United States 01.08.2018
Subjects:
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Carcinoma, Ductal, Breast - metabolism
Carcinoma, Ductal, Breast - pathology
Cell Adhesion
Cell Line, Tumor
Cell Movement
Connective Tissue Growth Factor - metabolism
Female
Fibroblasts - metabolism
Fibroblasts - pathology
Humans
Models, Biological
Oxidative Stress
rho-Associated Kinases - metabolism
Signal Transduction
Transcription Factors - metabolism
Tumor Microenvironment
Vascular Endothelial Growth Factor A - metabolism
Tumor microenvironment
Mass Spectrometry
Secretome
Click chemistry
Metastasis
reciprocal signaling
fibroblast activation
ISSN:1535-9484, 1535-9484
Online Access:Get more information
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Summary:Fibroblast activation is associated with tumor progression and implicated in metastasis, but the initial triggering signals required to kick-start this process remain largely unknown. Because small cancerous lesions share limited physical contact with neighboring fibroblasts, we reasoned the first tumor-derived signal for fibroblast activation should be secreted and diffusible. By pulsed metabolic labeling and click-chemistry based affinity enrichment, we sieved through the ductal carcinoma secretome for potential fibroblast activators. Using immuno-depletion/supplementation assays on various secreted factors, we pinpointed that tumor-secreted CTGF/VEGFA alone is sufficient to activate paired mammary fibroblasts from the same patient via ROCK1 and JunB signaling. Fibroblasts activated in this manner are distinct in morphology, growth, and adopt a highly tumor-like secretion profile, which in turn promotes tumor migration by counteracting oxidative and lactate stress. These findings reveal a profound division-of-labor between normal and cancer cells under the directive of the latter, and allude to potential metastatic prevention through inhibiting local fibroblast activation.
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ISSN:1535-9484
1535-9484
DOI:10.1074/mcp.RA118.000708