Effect of transdifferentiation on pancreatic ductal adenocarcinoma cells

Abstract

Pancreatic ductal adenocarcinomas (PDAC) represent the fourth leading cause of cancer-related deaths in the world. The 5-year survival rate of patients is 9%, and this is largely due to the great metastatic potential of this type of tumor.Different studies have shown that ectopic expression of specific transcription factors can successfully transdifferentiate pancreatic tumor cells from the exocrine to the endocrine lineage. Our aim was to analyze the effect of the exocrine-endocrine transdifferentiation of PDAC in relation to their migratory phenotype, and to develop an in vivo model for pancreatic cancer studies.We compared the gene expression profiles of ductal and endocrine pancreatic cells through the analysis of single cell RNA-seq. We identified 371 genes that are expressed at least twice as much in ductal as in endocrine pancreatic cells and performed a functional analysis of ontologies and signaling pathways (GO and KEGG). 54 genes were identified by both strategies as potentially related to tumor aggressiveness through characteristics such as cell migration and cell adhesion. Additionally, PANC-1 and SW1990 cells were implanted on the chorioallantoic membrane (CAM) of chick embryos, and tumor growth was analyzed at different stages. We found significant tumor growth 10 days after implantation. In order to induce transdifferentiation, PANC-1 cells were treated with BRD7552 for either 4 or 9 days, and migration rates were analyzed by wound healing assays. Significant decreases in migration rates were observed, whereas MTT assays showed no significant differences.In this work we identified genes involved in transdifferentiated cell phenotype, we revealed the inhibited migratory potential of transdifferentiated cells, and we established an alternative in vivo model for the study of PDAC based on cell implantation on the CAM of the chick embryo, well-suited for the in vivo evaluation of the effects of drugs on tumor growth, invasiveness, and metastatic potential.