Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development. Acid-adaptation-induced gain of cancerous traits was further increased p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt- and Transforming growth factor-beta (TGF beta) signaling, as well as expression of the Na+/H+ exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, stimulation with TGF beta I increased growth of WT control spheroids, and inhibition of TGF beta signaling tended to limit growth under acidic conditions only. Our results indicate that a complex crosstalk between tumor acidosis, ECM composition and genotype contributes to PDAC development. The findings may guide future strategies for acidosis-targeted therapies. Published under an exclusive license by AIP Publishing.

Automated summary

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited treatment options and increasing prevalence worldwide. This study reveals a complex interplay between tumor acidosis, extracellular matrix composition, and genotype in PDAC development. The findings may provide guidance for future acidosis-targeted therapies.