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Oncogene. 2018 Mar;37(10):1340-1353. doi: 10.1038/s41388-017-0038-6. Epub 2017 Dec 19.

GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers.

Author information

1
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
2
Cancer Therapeutics Research Laboratory, National Cancer Centre, Singapore, Singapore.
3
Mouse Models for Human Cancer Unit, Institute of Molecular and Cell Biology, Singapore, Singapore.
4
Department of Surgical Oncology, National Cancer Centre, Singapore, Singapore.
5
Advanced Molecular Pathology Laboratory, Singapore, Singapore.
6
Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore.
7
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
8
IZKF Junior Research Group, Friedrich-Alexander-Universitaet Erlangen-Nuernberg, Erlangen, Germany.
9
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore. patrick.casey@duke-nus.edu.sg.
10
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, USA. patrick.casey@duke-nus.edu.sg.
11
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore. gopaliyer@nccs.com.sg.
12
Cancer Therapeutics Research Laboratory, National Cancer Centre, Singapore, Singapore. gopaliyer@nccs.com.sg.
13
Department of Surgical Oncology, National Cancer Centre, Singapore, Singapore. gopaliyer@nccs.com.sg.

Abstract

Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of-care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs.

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