Crosstalk between tumor acidosis, p53, and extracellular matrix regulates pancreatic cancer aggressiveness
Menée à l'aide de lignées cellulaires et de sphéroïdes de cancer du pancréas, cette étude met en évidence un mécanisme par lequel les interactions entre l'acidose tumorale, la protéine p53 et la matrice extracellulaire contribuent au développement tumoral
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 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-
β (TGFβ) signaling, and expression of the Na+/H+ exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, addition of TGFβI increased growth of WT control spheroids, and inhibition of TGFβ signaling tended to inhibit 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.