Abstract
It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 4 / genetics
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Activating Transcription Factor 4 / metabolism
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Animals
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology*
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Cancer-Associated Fibroblasts / metabolism
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Cancer-Associated Fibroblasts / pathology*
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cells, Cultured
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Cellular Reprogramming*
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Disease Models, Animal
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Endoplasmic Reticulum / metabolism
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Extracellular Matrix Proteins / genetics
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Extracellular Matrix Proteins / metabolism*
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Female
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Humans
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Mice
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Paracrine Communication
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eIF-2 Kinase / genetics
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eIF-2 Kinase / metabolism*
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism*
Substances
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ATF4 protein, human
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CRELD2 protein, human
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Cell Adhesion Molecules
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Extracellular Matrix Proteins
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Activating Transcription Factor 4
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EIF2AK3 protein, human
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ROCK1 protein, human
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ROCK2 protein, human
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eIF-2 Kinase
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rho-Associated Kinases