Turning Down Oxygen to Turn Up Inflammation in CAFs

Pancreatic ductal adenocarcinoma (PDAC) contains a desmo-plastic stroma that limits blood perfusion and thus the delivery of nutrients, oxygen, and even therapeutics, creating a hypoxic microenvironment that resists nearly all forms of treatment, including immunomodulating therapy. Cancer-associated fibro-blasts (CAF) are the main cellular components and producers of stroma in PDAC. Interestingly, CAFs exist as functionally diverse subpopulations derived from distinct lineages, some of which can be either inflammatory (iCAF) or myofibroblastic (myCAF). While previous work has suggested a link between hypoxia and the iCAF phenotype, direct experimental evidence is lacking. In this issue of Cancer Research, Schwoeurorer and colleagues investigate the role of hypoxia and hypoxia-inducible factor-1a (HIF1a) in maintaining fibroblast heterogeneity and promoting tumor pro-gression in PDAC. The authors use a combination of in vitro and orthotopic techniques to identify a strong role for hypoxia in combination with tumor-derived cytokines in maintaining an iCAF phenotype highlighted by IL6 expression. The authors use an innovative in vitro system to simulate oxygen gradients and use these methods to support their assertions regarding hypoxia as a proinflammatory state. These findings suggest that HIF1a promotes the generation of iCAFs, providing novel insight into CAF heterogeneity.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) has a dense stroma that restricts blood perfusion and nutrient delivery, creating a hypoxic microenvironment. Cancer-associated fibroblasts (CAF) are the main cellular components and producers of stroma in PDAC. This study investigates the role of hypoxia and hypoxia-inducible factor-1a (HIF1a) in maintaining fibroblast heterogeneity and promoting tumor progression in PDAC.