Dataset Information

RhoJ controls EMT associated resistance to chemotherapy

ABSTRACT: The resistance of cancer cells to therapy is responsible for the death of most cancer patients. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma (SCC) undergoing spontaneous EMT during tumorigenesis, we found that EMT tumor cells were highly resistant to a wide range of anti-cancer therapy both in-vivo and in-vitro. Using gain and loss of function in vitro and in vivo, we uncovered that RhoJ, a small GTPase preferentially expressed in EMT cancer cells, controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RhoJ regulates EMT associated resistance to chemotherapy by promoting DNA damage response and the formation of new replication forks allowing tumor cells to repair DNA lesions more rapidly and survive under the replicative stress induced by chemotherapy. Using affinity-purification followed by mass spectrometry, we found that RhoJ interacts with proteins regulating nuclear actin and the inhibition of actin polymerization sensitizes EMT tumor cells to chemotherapy induced cell death in a Rhoj dependent manner. Altogether, our study uncovers the role and the mechanisms by which RhoJ acts as a key regulator of EMT associated resistance to chemotherapy.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Sara Dufour

LAB HEAD: Cédric Blanpain

PROVIDER: PXD038278 | Pride | 2023-01-13

REPOSITORIES: Pride

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			Action	DRS
	H090589_2p_WNE25_PM2PRC-5676_Blanpain_1.raw	Raw
	H090591_2p_WNE25_PM2PRC-5676_Blanpain_4.raw	Raw
	H090597_2p_WNE25_PM2PRC-5676_Blanpain_13.raw	Raw
	H090599_2p_WNE25_PM2PRC-5676_Blanpain_16.raw	Raw
	H090609_2p_WNE25_PM2PRC-5676_Blanpain_2_20220409023724.raw	Raw

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RHOJ controls EMT-associated resistance to chemotherapy.

Debaugnies Maud M Rodríguez-Acebes Sara S Blondeau Jeremy J Parent Marie-Astrid MA Zocco Manuel M Song Yura Y de Maertelaer Viviane V Moers Virginie V Latil Mathilde M Dubois Christine C Coulonval Katia K Impens Francis F Van Haver Delphi D Dufour Sara S Uemura Akiyoshi A Sotiropoulou Panagiota A PA Méndez Juan J Blanpain Cédric C

Nature 20230322 7955

The resistance of cancer cells to therapy is responsible for the death of most patients with cancer<sup>1</sup>. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells<sup>2,3</sup>. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to ...[more]

PMID: 36949199

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Project description:Epithelial/mesenchymal transition (EMT) is associated with loss of cell adhesion molecules, such as E-cadherin, and increased invasion, migration, and proliferation in epithelial cancers. In non-small cell lung cancer (NSCLC), EMT is associated with greater resistance to EGFR inhibitors. However, its potential to predict response to other targeted drugs or chemotherapy has not been well characterized. The goal of this study was to develop a robust, platform-independent EMT gene expression signature and to investigate the association of EMT and drug response in NSCLC. A 76-gene EMT signature was derived in 54 DNA-fingerprinted NSCLC cell lines and tested in an independent set of cell lines and in NSCLC patients from the BATTLE clinical trial. The signature classified cell lines as epithelial or mesenchymal independent of the microarray platform and correlated strongly with E-cadherin protein levels, as measured by reverse phase protein array. Higher protein expression of Rab25 (in epithelial lines) and Axl (in mesenchymal lines), two signature genes associated with in EMT in other cancer types, was also confirmed. Mesenchymal cell lines demonstrated significantly greater resistance to EGFR inhibition, independent of EGFR mutation status and were more resistant to drugs targeting the PI3K/Akt pathway. We observed no association between EMT and response to cytotoxic chemotherapies, including cisplatin, pemetrexed, and docetaxel monotherapy and/or doublets (p-values ≥0.2). In NSCLC patients, the EMT signature predicted 8-week disease control in the erlotinib arm, but not in other treatment arms. In conclusion, we have developed a robust EMT signature that predicts resistance to EGFR inhibitors and PI3K/Akt pathway inhibitors. Gene expression profiles were measured in 131 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EMT gene expression signature trained in cell lines and independant of the microarray platform.