Role of non-coding RNAs in tumor progression and metastasis in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with an overall 5-year survival rate of less than 10%. The 1-year survival rate of patients with locally advanced or metastatic disease is abysmal. The aggressive nature of cancer cells, hypovascularization, extensive desmoplastic stroma, and immunosuppressive tumor microenvironment (TME) endows PDAC tumors with multiple mechanisms of drug resistance. With no obvious genetic mutation(s) driving tumor progression or metastatic transition, the challenges for understanding the biological mechanism(s) of these processes are paramount. A better understanding of the molecular and cellular mechanisms of these processes could lead to new diagnostic tools for patient management and new targets for therapeutic intervention. microRNAs (miRNAs) are an evolutionarily conserved gene class of short non-coding regulatory RNAs. miRNAs are an extensive regulatory layer that controls gene expression at the posttranscriptional level. This review focuses on preclinical models that functionally dissect miRNA activity in tumor progression or metastatic processes in PDAC. Collectively, these studies suggest an influence of miRNAs and RNA-RNA networks in the processes of epithelial to mesenchymal cell transition and cancer cell stemness. At a cell-type level, some miRNAs mainly influence cancer cell–intrinsic processes and pathways, whereas other miRNAs predominantly act in distinct cellular compartments of the TME to regulate fibroblast and immune cell functions and/or influence other cell types’ function via cell-to-cell communications by transfer of extracellular vesicles. At a molecular level, the influence of miRNA-mediated regulation often converges in core signaling pathways, including TGF-β, JAK/STAT, PI3K/AKT, and NF-κB.