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.
Highlights
Treatment failure is a significant cause of death in solid tumors
GNA13 is a prognostic biomarker of survival and metastasis
Immunoblot analysis of GNA13 protein levels of a panel of head and neck squamous cell carcinoma (HNSCC) patient-derived cell lines showed higher GNA13 expression in cell lines derived from tumors taken from patients that went on to develop distant metastasis (HN19, HN43, and HN90), with no variation seen in the ortholog GNA12 (Figs. 1d and e)
Summary
Treatment failure (primary or secondary) is a significant cause of death in solid tumors. The identification of the TIC subpopulation of cancer cells have been aided by the use of surface markers, including CD44 in breast and head and neck, CD133 in colorectal and CD166 in lung cancers, respectively, and the activity of enzymes such as aldehyde dehydrogenase (ALDH1) [5,6,7] Subpopulations identified using these markers have increased potential for tumor-initiation, distant metastases, and resistance to multiple cytotoxic drugs and radiation therapy [8]. The volume of tumor xenografts in NOD/SCID mice using GNA13 overexpressing NCC-HN26 cells with/without cisplatin treatment, compared to vector control is shown (Top panel). We uncovered a crucial role of GNA13 in the acquisition of TIC-like phenotypes and therapeutic response in solid tumors, and found that GNA13 expression levels correlate with poor clinical outcomes in these cancers
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