Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness. Issue 6 (1st December 2022)

• Record Type: Journal Article
• Authors: Czaplinska, Dominika; Ialchina, Renata; Andersen, Henriette Berg; Yao, Jiayi; Stigliani, Arnaud; Dannesboe, Johs; Flinck, Mette; Chen, Xiaoming; Mitrega, Jakub; Gnosa, Sebastian Peter; Dmytriyeva, Oksana; Alves, Frauke; Napp, Joanna; Sandelin, Albin; Pedersen, Stine Falsig
• Is Part Of: International journal of cancer. Volume 152:Issue 6(2023)
• Page Start: 1210
• Page End: 1225
• Publication Date: 2022-12-01
• Subjects: extracellular matrix -- invasion -- organotypic culture -- spheroids -- tumor microenvironment; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.34367
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: 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 by p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt‐ and Transforming growth factor‐β (TGFβ) 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 TGFβI increased growth of WT control spheroids, and inhibition of TGFβ 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. Abstract : What's new? Pancreatic ductal adenocarcinoma (PDAC) is characterized by specific driver mutations and by the presence of extracellular acidosis within a dense, fibrotic, extracellular matrix (ECM). While these features are independently linked to increased PDAC invasiveness, whether genotype impacts the pancreatic tumor microenvironment remains unclear. Our study shows that three‐dimensional and anchorage‐independent PDAC cell growth and PDAC progression are enhanced by acid adaptation, specifically when normal ECM pH is reestablished, as occurs during vascularization and metastasis. The findings suggest that interplay between acidosis, ECM composition and driver mutations strongly influences PDAC aggressiveness, with possible relevance for the development of novel therapeutic strategies.