Renata Ialchina: Interactions between microenvironmental acidity and PDAC driver mutations studied in 3D organotypic culture Date: 14-06-2023    Supervisor: Stine Falsig Pedersen

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease which is predicted to become the second cancer-related cause of death globally by 2030. PDAC development is characterized by a desmoplastic, acidic and hypoxic tumor microenvironment, which is suggested to contribute to epithelial-mesenchymal transition (EMT), metabolic changes, and drug resistance. Although PDAC progression is described to involve series of driver mutations such as KRAS, TP53, SMAD4, CDKN2A, the molecular mechanism of how the interplay between chronic acidosis and driver mutations impact tumorigenesis remains essentially unknown.

Collectively, the work of Renata's PhD thesis demonstrates that chronic acid adaptation and loss of the tumor suppressor p53 increase pH regulation capacity, 3D growth, drug resistance, invasiveness and stem cell-like phenotype in pancreatic cancer cells, compared to respective controls. These findings extend the current understanding of how chronic acidosis and driver mutations favor tumor progression, of potential relevance for development of new acidosis-targeted therapeutics.