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

Suhail Ahmed Kabeer Rasheed; Hui Sun Leong; Manikandan Lakshmanan; Anandhkumar Raju; Dhivya Dadlani; Fui Teen Chong; Nicholas B. Shannon; Ravisankar Rajarethinam; Thakshayeni Skanthakumar; Ern Yu Tan; Jacqueline Siok Gek Hwang; Kok Hing Lim; Daniel Shao Weng Tan; Paolo Ceppi; Mei Wang; Vinay Tergaonkar; Patrick J. Casey; N. Gopalakrishna Iyer

doi:10.1038/s41388-017-0038-6

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

Suhail Ahmed Kabeer Rasheed, Hui Sun Leong, Manikandan Lakshmanan, Anandhkumar Raju, Dhivya Dadlani, Fui Teen Chong, Nicholas B. Shannon, Ravisankar Rajarethinam, Thakshayeni Skanthakumar, Ern Yu Tan, Jacqueline Siok Gek Hwang, Kok Hing Lim, Daniel Shao Weng Tan, Paolo Ceppi, Mei Wang, Vinay Tergaonkar, Patrick J. Casey, N. Gopalakrishna Iyer

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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.

Original language	English
Journal	Oncogene
Volume	37
Issue number	10
Pages (from-to)	1340-1353
Number of pages	14
ISSN	0950-9232
DOIs	https://doi.org/10.1038/s41388-017-0038-6
Publication status	Published - 2018
Externally published	Yes

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10.1038/s41388-017-0038-6Licence: CC BY

Open Access VersionFinal published version, 4.23 MBLicence: CC BY

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Rasheed, S. A. K., Leong, H. S., Lakshmanan, M., Raju, A., Dadlani, D., Chong, F. T., Shannon, N. B., Rajarethinam, R., Skanthakumar, T., Tan, E. Y., Hwang, J. S. G., Lim, K. H., Tan, D. S. W., Ceppi, P., Wang, M., Tergaonkar, V., Casey, P. J., & Iyer, N. G. (2018). GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers. Oncogene, 37(10), 1340-1353. https://doi.org/10.1038/s41388-017-0038-6

@article{f7dfab7e85c94aafb65e77d56a412bab,

title = "GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers",

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.",

author = "Rasheed, {Suhail Ahmed Kabeer} and Leong, {Hui Sun} and Manikandan Lakshmanan and Anandhkumar Raju and Dhivya Dadlani and Chong, {Fui Teen} and Shannon, {Nicholas B.} and Ravisankar Rajarethinam and Thakshayeni Skanthakumar and Tan, {Ern Yu} and Hwang, {Jacqueline Siok Gek} and Lim, {Kok Hing} and Tan, {Daniel Shao Weng} and Paolo Ceppi and Mei Wang and Vinay Tergaonkar and Casey, {Patrick J.} and Iyer, {N. Gopalakrishna}",

year = "2018",

doi = "10.1038/s41388-017-0038-6",

language = "English",

volume = "37",

pages = "1340--1353",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer",

number = "10",

}

Rasheed, SAK, Leong, HS, Lakshmanan, M, Raju, A, Dadlani, D, Chong, FT, Shannon, NB, Rajarethinam, R, Skanthakumar, T, Tan, EY, Hwang, JSG, Lim, KH, Tan, DSW, Ceppi, P, Wang, M, Tergaonkar, V, Casey, PJ & Iyer, NG 2018, 'GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers', Oncogene, vol. 37, no. 10, pp. 1340-1353. https://doi.org/10.1038/s41388-017-0038-6

TY - JOUR

T1 - GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers

AU - Rasheed, Suhail Ahmed Kabeer

AU - Leong, Hui Sun

AU - Lakshmanan, Manikandan

AU - Raju, Anandhkumar

AU - Dadlani, Dhivya

AU - Chong, Fui Teen

AU - Shannon, Nicholas B.

AU - Rajarethinam, Ravisankar

AU - Skanthakumar, Thakshayeni

AU - Tan, Ern Yu

AU - Hwang, Jacqueline Siok Gek

AU - Lim, Kok Hing

AU - Tan, Daniel Shao Weng

AU - Ceppi, Paolo

AU - Wang, Mei

AU - Tergaonkar, Vinay

AU - Casey, Patrick J.

AU - Iyer, N. Gopalakrishna

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1038/s41388-017-0038-6

DO - 10.1038/s41388-017-0038-6

M3 - Journal article

C2 - 29255247

AN - SCOPUS:85038409561

SN - 0950-9232

VL - 37

SP - 1340

EP - 1353

JO - Oncogene

JF - Oncogene

IS - 10

ER -

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

Abstract

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