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Simple Summary  For patients with metastatic pancreatic ductal adenocarcinoma (PDAC) there is currently no cure; hence, novel effective therapies are desperately needed. Among PDAC patients, the tumor cell phenotypes are heterogeneous as a result of epithelial–mesenchymal transition, a process that endows them with the ability to metastasize, resist therapy, and generate cancer stem cells. The heightened plasticity of quasimesenchymal and potentially metastatic tumor cells may, however, also be exploited for their transdifferentiation into benign, highly differentiated or post-mitotic cells. Since PDAC patients often have a need for replacement of insulin-producing cells, conversion of tumor cells with a ductal/exocrine origin to endocrine β cell-like cells is an attractive therapeutic option. Successful transdifferentiation into insulin-producing cells has been reported for the quasimesenchymal cell line PANC-1; however, the mechanistic basis of this transformation process is unknown. Here, we show that the small GTPases, RAC1 and RAC1b control this process by antagonistic regulation of stemness genes.Abstract  Epithelial–mesenchymal transition (EMT) is a driving force for tumor growth, metastatic spread, therapy resistance, and the generation of cancer stem cells (CSCs). However, the regained stem cell character may also be exploited for therapeutic conversion of aggressive tumor cells to benign, highly differentiated cells. The PDAC-derived quasimesenchymal-type cell lines PANC-1 and MIA PaCa-2 have been successfully transdifferentiated to endocrine precursors or insulin-producing cells; however, the underlying mechanism of this increased plasticity remains elusive. Given its crucial role in normal pancreatic endocrine development and tumor progression, both of which involve EMT, we analyzed here the role of the small GTPase RAC1. Ectopic expression in PANC-1 cells of dominant negative or constitutively active mutants of RAC1 activation blocked or enhanced, respectively, the cytokine-induced activation of a ductal-to-endocrine transdifferentiation transcriptional program (deTDtP) as revealed by induction of the NEUROG3, INS, SLC2A2, and MAFA genes. Conversely, ectopic expression of RAC1b, a RAC1 splice isoform and functional antagonist of RAC1-driven EMT, decreased the deTDtP, while genetic knockout of RAC1b dramatically increased it. We further show that inhibition of RAC1 activation attenuated pluripotency marker expression and self-renewal ability, while depletion of RAC1b dramatically enhanced stemness features and clonogenic potential. Finally, rescue experiments involving pharmacological or RNA interference-mediated inhibition of RAC1 or RAC1b, respectively, confirmed that both RAC1 isoforms control the deTDtP in an opposite manner. We conclude that RAC1 and RAC1b antagonistically control growth factor-induced activation of an endocrine transcriptional program and the generation of CSCs in quasimesenchymal PDAC cells. Our results have clinical implications for PDAC patients, who in addition to eradication of tumor cells have a need for replacement of insulin-producing cells.

cancers

Activation of a Ductal-to-Endocrine Transdifferentiation Transcriptional Program in the Pancreatic Cancer Cell Line PANC-1 Is Controlled by RAC1 and RAC1b through Antagonistic Regulation of Stemness Factors