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PDAC is characterized by frequent driver mutations including <jats:italic>KRAS<\/jats:italic> and <jats:italic>TP53<\/jats:italic> (p53)<jats:italic>,<\/jats:italic> 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\u2010dimensional (3D) culture, adhesion\u2010independent colony formation and invasive outgrowth. This pattern of acidosis\u2010induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen\u2010I and combination thereof, mimicking early and later stages of PDAC development. Acid\u2010adaptation\u2010induced gain of cancerous traits was further increased by p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt\u2010 and Transforming growth factor\u2010\u03b2 (TGF\u03b2) signaling, as well as expression of the Na<jats:sup>+<\/jats:sup>\/H<jats:sup>+<\/jats:sup> exchanger NHE1, were increased by acid adaptation. Whereas Akt inhibition decreased spheroid growth regardless of treatment and genotype, stimulation with TGF\u03b2I increased growth of WT control spheroids, and inhibition of TGF\u03b2 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. 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