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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| Vydáno v: | Molecular & cellular proteomics Ročník 17; číslo 8; s. 1502 |
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| Hlavní autoři: | , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
01.08.2018
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| ISSN: | 1535-9484, 1535-9484 |
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| Abstract | 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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| AbstractList | 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. 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.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. |
| Author | Berkers, Celia R Wu, Wei Zaal, Esther A Lemeer, Simone Heck, Albert J R |
| Author_xml | – sequence: 1 givenname: Wei surname: Wu fullname: Wu, Wei organization: §Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands – sequence: 2 givenname: Esther A surname: Zaal fullname: Zaal, Esther A organization: From the ‡Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands – sequence: 3 givenname: Celia R surname: Berkers fullname: Berkers, Celia R organization: From the ‡Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands – sequence: 4 givenname: Simone orcidid: 0000-0002-6230-9471 surname: Lemeer fullname: Lemeer, Simone organization: §Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands – sequence: 5 givenname: Albert J R orcidid: 0000-0002-2405-4404 surname: Heck fullname: Heck, Albert J R email: a.j.r.heck@uu.nl organization: §Netherlands Proteomics Centre, Padualaan 8, 3584 CH Utrecht, the Netherlands |
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| Copyright | 2018 Wu et al. |
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| Keywords | Tumor microenvironment Mass Spectrometry Secretome Click chemistry Metastasis reciprocal signaling fibroblast activation |
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| SubjectTerms | 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 |
| Title | CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation |
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