Three deadly P’s: Protons and P53 loss in Pancreatic cancer

Stine Falsig Pedersen, Professor at Dept of Biology, Section for Cell Biology and Physiology, University of Copenhagen, Denmark

Tumors develop heterogeneous, but profoundly acidic microenvironments, owing to the combination of increased metabolic acid production and disordered perfusion. This facilitates further disease progression through the influence of intra- and extracellular pH disturbances on multiple aspects of tumour biology, ranging from proliferation over metabolism and cellular signaling to immune surveillance. As a selection pressure, extracellular acidosis favours the expansion of acid-resistant cancer cells, which are typically associated with aggressive phenotypes. Our ongoing work explores the mechanisms involved in this acidosis-driven aggressiveness, with an emphasis on how microenvironment acidosis synergizes with oncogenic mutations in KRAS and p53 to drive aggressive traits in pancreatic cancer models. Here, I present a brief overview of our work on unraveling the impact of tumor acidosis on disease aggressiveness, and I discuss possible therapeutic avenues.