Loss of ARID1A Promotes Epithelial–Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress

Abstract

Cellular de-differentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anti-cancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in ARID1A represent one of the most frequent molecular alterations in human cancers. ARID1A mutations occur in ~10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here we demonstrate that loss of ARID1A promotes an epithelial-mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both in vitro and in vivo. While loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in ARID1A associated with protein loss exhibits potential as a biomarker for PDAC patients who may benefit by HSP90targeting drugs treatment. Statement of Significance This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents. Research.

ARID1A serves as a receivable biomarker for the resistance to EGFR-TKIs in non-small cell lung cancer

“…It suggested that ARID1A alterations are associated with the expression signature of EMT promoters related genes (Wilson et al 2019). Furthers studies also confirmed the role of ARID1A expression loss in modulating the biomarkers for EMT process through in vitro and in vivo experiments (Wang et al 2019(Wang et al ,2020bSomsuan et al 2019;Tomihara et al 2021). The expression loss of ARID1A upregulates the expression of fibronectin, vimentin and N-cadherin, while downregulates the expression of E-cadherin, which enables the transformation of the tumor cell phenotype to mesenchymal cell type characterized by the loss of cell polarity and the changes of cell morphology.…”

Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

“…Mechanistically the reduced tumor latency seemed to be linked to the elevated protein levels of Myc [ 152 ]. Furthermore, Arid1a knockdown in pancreatic cancer cell lines induced a phenotypic shift to a more mesenchymal state, associated with elevated expression of EMT related markers, such as vimentin and N-cadherin [ 153 ].…”

Targeting SWI/SNF metabolic vulnerabilities in cancer

“…Delattre further speculated that the clear cell phenotype might be indicative of SWI/SNF aberrations in other rare tumors with this histotype that have not yet been characterized in large-scale genomic studies. enocarcinomas characterized by downregulation of SMARCB1 and other members of the SWI/SNF complex resulted in undifferentiated/sarcoma-like transformation with aggressive behavior (56,57). Upon SMARCB1 downregulation, pancreatic cancer cells exhibited a defective regulation of proteostasis; such disruption of the proteostatic equilibrium leads to specific vulnerabilities of mesenchymal pancreatic cancer cells that can be exploited therapeutically with clinically available drugs (56,57).…”

“…enocarcinomas characterized by downregulation of SMARCB1 and other members of the SWI/SNF complex resulted in undifferentiated/sarcoma-like transformation with aggressive behavior (56,57). Upon SMARCB1 downregulation, pancreatic cancer cells exhibited a defective regulation of proteostasis; such disruption of the proteostatic equilibrium leads to specific vulnerabilities of mesenchymal pancreatic cancer cells that can be exploited therapeutically with clinically available drugs (56,57). These results demonstrated yet another way in which SWI/SNF mutations lead to metabolic abnormalities and vulnerabilities in cancer that can be targeted therapeutically.…”