Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells

Changhwan Yoon, Soo Jeong Cho, Bülent Arman Aksoy, Do Joong Park, Nikolaus Schultz, Sandra W. Ryeom, Sam S. Yoon

Research output: Contribution to journalArticle

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Abstract

Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA. Experimental Design: We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. Results: RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78% to 81%. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40% to 50%, RhoA inhibition by 32% to 60%, and the combination by 77% to 83%. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612). Conclusions: RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse overall survival in DGA patients, and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus, the RhoA pathway is a promising new target in DGA patients.

Original languageEnglish
Pages (from-to)971-983
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number4
DOIs
StatePublished - 15 Feb 2016

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Neoplastic Stem Cells
Stomach
Adenocarcinoma
Drug Therapy
Heterografts
Cisplatin
Stomach Neoplasms
Neoplasms
Cell Line
Stem Cell Factor
Survival
Fluorouracil
Small Interfering RNA
Research Design
Transcription Factors
Phenotype
Mutation

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Yoon, Changhwan ; Cho, Soo Jeong ; Aksoy, Bülent Arman ; Park, Do Joong ; Schultz, Nikolaus ; Ryeom, Sandra W. ; Yoon, Sam S. / Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 4. pp. 971-983.
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title = "Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells",
abstract = "Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA. Experimental Design: We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. Results: RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78{\%} to 81{\%}. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40{\%} to 50{\%}, RhoA inhibition by 32{\%} to 60{\%}, and the combination by 77{\%} to 83{\%}. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612). Conclusions: RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse overall survival in DGA patients, and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus, the RhoA pathway is a promising new target in DGA patients.",
author = "Changhwan Yoon and Cho, {Soo Jeong} and Aksoy, {B{\"u}lent Arman} and Park, {Do Joong} and Nikolaus Schultz and Ryeom, {Sandra W.} and Yoon, {Sam S.}",
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Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells. / Yoon, Changhwan; Cho, Soo Jeong; Aksoy, Bülent Arman; Park, Do Joong; Schultz, Nikolaus; Ryeom, Sandra W.; Yoon, Sam S.

In: Clinical Cancer Research, Vol. 22, No. 4, 15.02.2016, p. 971-983.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chemotherapy resistance in diffuse-type gastric adenocarcinoma is mediated by RhoA activation in cancer stem-like cells

AU - Yoon, Changhwan

AU - Cho, Soo Jeong

AU - Aksoy, Bülent Arman

AU - Park, Do Joong

AU - Schultz, Nikolaus

AU - Ryeom, Sandra W.

AU - Yoon, Sam S.

PY - 2016/2/15

Y1 - 2016/2/15

N2 - Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA. Experimental Design: We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. Results: RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78% to 81%. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40% to 50%, RhoA inhibition by 32% to 60%, and the combination by 77% to 83%. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612). Conclusions: RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse overall survival in DGA patients, and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus, the RhoA pathway is a promising new target in DGA patients.

AB - Purpose: The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbors mutations in RHOA, but little is known about the role of RhoA in DGA. Experimental Design: We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. Results: RhoA activity was higher in DGA compared with IGA cell lines and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSCs) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78% to 81%. DGA spheroid cells had 3- to 5-fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40% to 50%, RhoA inhibition by 32% to 60%, and the combination by 77% to 83%. In 288 patient tumors, increased RhoA activity correlated with worse overall survival in DGA patients (P = 0.017) but not in IGA patients (P = 0.612). Conclusions: RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse overall survival in DGA patients, and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus, the RhoA pathway is a promising new target in DGA patients.

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DO - 10.1158/1078-0432.CCR-15-1356

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