Emerging frontiers in pancreatic cancer research

Abstract

We review recent literature with a view to forge an integrative understanding of the molecular, cellular and extracellular milieu of pancreatic cancer, and discuss them in the context of development of novel, personalized therapeutic options. Pancreatic tumorigenesis, examined using genetically engineered mouse models, appears to be driven by local inflammation, in concert with the 'big four' mutations involving oncogenic KRAS, SMAD4, CDKN2A, and TP53, through induction of epithelial-to-mesenchymal transition (EMT) and cancer stem cells, and accompanied by metastasis. High-throughput sequencing of pancreatic ductal adenocarcinoma as well as neuroendocrine tumors and rarer subtypes of cancers of the pancreas has revealed several novel mutations in genes like PALB2, guanine nucleotide-binding protein, alpha stimulating, death-domain-associated protein, α thalassemia/mental retardation syndrome X linked, switch/sucrose nonfermentable pathway related, and in genes in the ubiquitin-dependent pathways such as USP9X. Therapeutic targeting of the tumor-stroma axis by cytokines and immune response modulators and the role of autophagy in pancreatic cancer are some other salient themes explored in the recent publications. Recent publications shed new light on the mutational landscape of pancreatic cancer and further delineate the distinctive pancreatic cancer-stroma ecosystem as determined by the dynamic interplay of inflammation, hallmark mutations, EMT, and cancer stem cells.