TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex.
Metastasis is a significant health issue. The standard mode of care is combination of chemotherapy and targeted therapeutics but the 5-year survival rate remains low. New/better drug targets that can improve outcomes of patients with metastatic disease are needed. Metastasis is a complex process, with each step conferred by a set of genetic aberrations. Mapping the molecular changes associated with metastasis improves our understanding of the etiology of this disease and contributes to the pipeline of targeted therapeutics. Here, phosphoproteomics of a xenograft-derived in vitro model comprising 4 isogenic cell lines with increasing metastatic potential implicated Transient Receptor Potential Vanilloid subtype 4 in breast cancer metastasis. TRPV4 mRNA levels in breast, gastric and ovarian cancers correlated with poor clinical outcomes, suggesting a wide role of TRPV4 in human epithelial cancers. TRPV4 was shown to be required for breast cancer cell invasion and transendothelial migration but not growth/proliferation. Knockdown of Trpv4 significantly reduced the number of metastatic nodules in mouse xenografts leaving the size unaffected. Overexpression of TRPV4 promoted breast cancer cell softness, blebbing, and actin reorganization. The findings provide new insights into the role of TRPV4 in cancer extravasation putatively by reducing cell rigidity through controlling the cytoskeleton at the cell cortex.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Wen Hsin
WH
Lee
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Lee Yee
LY
Choong
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Naing Naing
NN
Mon
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
SsuYi
S
Lu
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore.
Qingsong
Q
Lin
Cancer Science Institute of Singapore, Singapore.
Brendan
B
Pang
National University Hospital, Department of Laboratory Medicine, Singapore.
Benedict
B
Yan
Mechanobiology Institute, National University of Singapore, Singapore.
Vedula Sri Ram
VS
Krishna
Department of Biomedical Engineering, National University of Singapore, Singapore.
Himanshu
H
Singh
Cancer Science Institute of Singapore, Singapore.
Tuan Zea
TZ
Tan
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, Singapore.
Jean Paul
JP
Thiery
Mechanobiology Institute, National University of Singapore, Singapore.|Department of Biomedical Engineering, National University of Singapore, Singapore.
Chwee Teck
CT
Lim
Duke-NUS Graduate Medical School, Singapore.
Patrick Boon Ooi
PB
Tan
Respiratorius AB, Lund, Sweden.
Martin
M
Johansson
Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany.
Christian
C
Harteneck
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.|National University Cancer Institute, National University Health System, Singapore.
Yoon Pin
YP
Lim
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D010748:Phosphopeptides / Q000032:analysis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D010748:Phosphopeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050916:TRPV Cation Channels; D002118:Calcium