Development of thymic tumor in [LSL:KrasG12D; Pdx1-CRE] mice, an adverse effect associated with accelerated pancreatic carcinogenesis

Abstract

Pancreatic Ductal AdenoCarcinoma (PDAC) represents about 90% of pancreatic cancers. It is one of the most aggressive cancer, with a 5-year survival rate below 10% due to late diagnosis and poor therapeutic efficiency. This bad prognosis thus encourages intense research in order to better understand PDAC pathogenesis and molecular basis leading to the development of innovative therapeutic strategies. This research frequently involves the KC (LSL:Kras^G12D;Pdx1-CRE) genetically engineered mouse model, which leads to pancreatic cancer predisposition. However, as frequently encountered in animal models, the KC mouse model also exhibits biases. Herein, we report a new adverse effect of Kras^G12D mutation in KC mouse model. In our hands, 10% of KC mice developed clinical signs reaching pre-defined end-points between 100- and 150-days post-parturition, and associated with large thymic mass development. Histological and genetic analyses of this massive thymus enabled us (1) to characterize it as a highly proliferative thymic lymphoma and (2) to detect the unexpected recombination of the Lox-STOP-Lox cassette upstream Kras^G12D allele and subsequent KRAS^G12D protein expression in all cells composing thymic masses. Finally, we highlighted that development of such thymic tumor was associated with accelerated pancreatic carcinogenesis, immune compartment disorganization, and in some cases, lung malignancies.