CONICET | Buscador de Institutos y Recursos Humanos

Pancreatic ductal adenocarcinoma (PDAC) represents a very aggressive type of pancreatic cancer (9% survival rate at 5 years). Ectopic expression of specific transcription factors can successfully transdifferentiate pancreatic tumor cells from the exocrine to the endocrine lineage. Specifically, PDX1 and Neurog3 promote transdifferentiation of PANC-1 cells from an exocrine to an endocrine beta-like phenotype, and their overexpression in PDAC patients increases survival rate. Therefore, our aim was to analyze the effect of the exocrine-endocrine transdifferentiation of PDAC cells on their aggressiveness. To induce transdifferentiation, PANC-1 cells were either treated with BRD7552 (a PDX1 inducer) for 9 days or transfected with a plasmid of expression of hNeurog3. No cytotoxic effect was observed by MTT nor Trypan Blue assays on treated cells. Wound healing assay showed a significant reduction in migration rate. Flow cytometry assay showed an increase in G1 phase in treated cells relative to control. Analysis of Ki67 immunostaining exhibited no significant difference in cell proliferation rates. Treated PANC-1 cells were implanted onto the chorioallantoic membrane of chick embryos and tumor growth was measured at different stages, observing decreased tumor size at day 7 post-implantation compared to control. Neurog3 transfection showed no morphological effect on PANC-1 cells. Through scRNA-seq and bulk RNA-seq analysis we identified genes associated with tumor aggressiveness in human ductal pancreatic cells and with unfavorable clinical parameters in PDAC patients. In conclusion, transdifferentiation through BRD7552 treatment affects cell cycle, and inhibits migratory potential in vitro and tumor growth in ovo.

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