title: Proton-sensing GPCR-YAP Signalling Promotes Cancer-associated Fibroblast Activation of Mesenchymal Stem Cells.
abstract: The pHs of extracellular fluids (ECFs) in normal tissues are commonly maintained at 7.35 to 7.45. The acidification of the ECF is one of the major characteristics of tumour microenvironment. In this study, we report that decreased extracellular pH promotes the transformation of mesenchymal stem cells (MSCs) into cancer-associated fibroblasts (CAFs), termed CAF activation. Furthermore, we demonstrate that GPR68, a proton-sensing G-protein-coupled receptor (GPCR), is required for the pH-dependent regulation of the differentiation of MSCs into CAFs. We then identify Yes-associated protein 1 (YAP) as a downstream effector of GPR68 for CAF activation. Finally, we show that knockdown of GPR68 in MSCs can prevent the CAF activation under cancer microenvironment. Systemic transplantation of GPR68-silenced MSCs suppresses in-situ tumour growth and prolong life span after cancer graft.
authors.affiliation: 1. Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China;
authors.forename: Hongyi
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 2. Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Shangchun
authors.initials: S
authors.lastname: Guo
authors.affiliation: 1. Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China;
authors.forename: Yuelei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 2. Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Yin
authors.affiliation: 1. Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China;
authors.forename: Wenjing
authors.initials: W
authors.lastname: Yin
authors.affiliation: 1. Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China;
authors.forename: Shicong
authors.initials: S
authors.lastname: Tao
authors.affiliation: 2. Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1. Department of Orthopaedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China;; 2. Institute of Microsurgery on Extremities, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000072645:Cancer-Associated Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011522:Protons; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486281:GPR68 protein, human; D010750:Phosphoproteins; D011522:Protons; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: GPCR; YAP; cancer; fibroblast.; pH; proton-sensing