The ever-changing landscape of pancreatic cancer stem cells

Over the past decade, the cancer stem cell (CSC) concept in solid tumors has gained enormous momentum as an attractive model to explain tumor heterogeneity. The model proposes that tumors contain a subpopulation of rare cancer cells with stem-like properties that maintain the hierarchy of the tumor and drive tumor initiation, progression, metastasis, and chemoresistance. The identification and subsequent isolation of CSCs in pancreatic ductal adenocarcinoma (PDAC) in 2007 provided enormous insight into this extremely metastatic and chemoresistant tumor and renewed hope for developing more specific therapies against this disease. Unfortunately, we have made only marginal advances in applying the knowledge learned to the development of new and more effective treatments for pancreatic cancer. The latter has been partly due to the lack of adequate in vitro and in vivo systems compounded by the use of markers that do not reproducibly nor exclusively select for an enriched CSC population. Thus, attempts to define a pancreatic CSC-specific genetic, epigenetic or proteomic signature has been challenging. Fortunately recent advances in the CSC field have overcome many of these challenges and have opened up new opportunities for developing therapies that target the CSC population. In this review, we discuss these current advances, specifically new methods for the identification and isolation of pancreatic CSCs, new insights into the metabolic profile of CSCs at the level of mitochondrial respiration, and the utility of genetically engineered mouse models as surrogate systems to both study CSC biology and evaluate CSC-specific targeted therapies in vivo.