In all components (bilateral serous borderline tumors, low-grade serous carcinoma and mesonephric-like adenocarcinoma), an identical KRAS mutation was detected (NM_004985.4): c.35G>A, p.(G12D) proving a clonal association between the serous and mesonephric-like components and excluding a collision neoplasm.
Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas.
Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) mice, where STAT3 was not hyperactivated.
Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1b(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice.
After microdissecting and testing the adenocarcinoma and neuroendocrine components separately, it was found that the adenocarcinoma was positive for KRAS G12C mutation and the neuroendocrine component was positive for KRAS G12D mutation.
Firstly, lentivirus-mediated transduction of KRAS(G12V), MYC and human papillomavirus 16 (HPV16) E6/E7 under the control of a tetracyclin-inducible promoter efficiently immortalized and transformed primary HPDECs, which gave rise to adenocarcinomas subcutaneously in an immune-deficient mouse xenograft model, depending on expression of the four genes.
Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas.