Oncogenic role of circBFAR in pancreatic cancer progression and chemoresistance

Pancreatic ductal adenocarcinoma (PDAC) lethality is mainly due to its chemoresistance and early invasion. These malignant characteristics are supported by both the presence of a dense Extracellular Matrix (ECM), which becomes ever more enriched in Collagen I as the tumor progresses, and the selection of the highly chemoresistant Cancer Stem Cells (CSCs). Circular RNAs (circRNAs) represent a new class of promising biomarkers for disease assessment and for developing novel anticancer drugs. Here we first analyzed the expression of circBFAR, which has been reported to be overexpressed in 2D cultures of PDAC cells, in both pancreatic normal cells and in a panel of PDAC parenchymal cells and their derived CSCs growing as organotypic cultures on different ECMs mimicking PDAC progression. RT-qPCR assays revealed that circBFAR is overexpressed in the tumor parenchymal cells compared to the normal cells and is even more highly expressed in the CSCs compared to the tumor parenchymal cells. Further, the CSCs upregulate circBFAR especially on a Matrigel-enriched ECM mimicking the early stages of PDAC progression. Lastly, on this ECM circBFAR silencing (i) decreases the ability of the tumor parenchymal cells to digest the ECM and (ii) modulates CSCs chemoresistance to GEM-C18, a novel prodrug of the gold standard chemotherapy Gemcitabine. Our data highlight a novel role for circBFAR in driving PDAC malignancy through the control of its early invasive abilities and chemoresistance.