Resumen de Exploiting Oxidative Phosphorylation to Promote Stem and Immunoevasive Properties of Pancreatic Cancer Stem Cells
Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 9% and is expected to become the second most lethal tumor by the year 2030. These alarming statistics can be attributed to the high metastatic and chemoresistant capacity of this tumor, and the ineffectiveness of conventional therapies to provide long-term progression-free survival (> 5 years). The latter is believed to be due, in large part, to the existence of a “stem”-like subpopulation of cells within the tumor known as cancer stem cells (CSCs), which have inherent plasticity, have been experimentally shown to be the initiators of the primary tumor, are able to evade chemotherapy, remain quiescent and metastasize to distant organs. To better understand the biology and plasticity of pancreatic CSCs, with the ultimate goal of eliminating them, we have initiated studies to dissect these cells at the molecular level.
Metabolic adaptation is believed to be one of the hallmarks of cancer cells. Interestingly, we published that against established dogma, pancreatic CSCs have a metabolism dependent on oxidative mitochondrial phosphorylation (OXPHOS) in contrast to non-CSCs, which depend on glycolytic metabolism (Warburg effect). Using this discovery to our advantage, we have developed a novel 2D in vitro system for long term enrichment of pancreatic CSCs that is amenable to drug screening and CSC-specific studies. Specifically, in the presence of galactose we can establish long-term 2D cultures of primary PDX-derived PDAC cultures enriched in PaCSCs. Compared to glucose, ATP yield from galactose is slower. Thus, due to ATP yield differences, non-PaCSCs cannot survive in galactose, while OXPHOS-dependent PaCSCs survive and become enriched. Moreover, under galactose condition, we show that primary PDAC cells are highly plastic, present an enrichment in CSC biomarkers and pluripotency-associated genes, enter into a slow-cycling/quiescent stage, increase mitochondrial networks and OXPHOS activity and are more invasiveness in vivo, the latter being due, in part, to the modulation of immune evasion markers, an aspect of PaCSCs biology that has been poorly studied to date.
In summary, this novel cell culture system could be potentially used to screen for novel CSC-specific inhibitors as well as new compounds directed towards cancer cell metabolism, an area of research that is gaining considerable attention, and based on the correlation observed with immune evasion, may synergize with immunotherapeutic approaches for improved and long-lasting antitumor outcomes.
