Dataset Information

Kras loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity

ABSTRACT: Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE277392 | GEO | 2024/09/22

REPOSITORIES: GEO

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Project description:K-ras mutations are observed in around 40% human colorectal adenomas and carcinomas and contribute to the pathogenesis of human and rodent colorectal tumour formation. Previously, we developed and characterised a strain of transgenic mice with inducible intestinal epithelial expression of K-rasVal12 via a Cre/LoxP system. To evaluate the influence of mutant K-ras on carcinogen-induced colorectal tumourigenesis, we induced neoplastic alterations in the large intestines of wild-type and K-rasVal12 mice using the colon-selective carcinogen 1, 2-dimethylhydrazine (DMH), which has been widely used to study chemically induced colorectal tumours that are histopathologically similar to those observed in humans. K-rasVal12 expression significantly promoted DMH-induced colorectal tumourigenesis: the average life span of the mice decreased from 38.52Â±1.97 weeks for 40 wild-type mice to 32.42Â±2.17 weeks for 26 K-rasVal12 mice (mean+SEM, P<0.05) and the large intestinal tumours increased from 2.27Â±0.15 per wild-type mouse to 3.85Â±0.20 in K-rasVal12 mice (mean+SEM, P<0.01). Adenomas from DMH-treated K-rasVal12 mice showed significantly higher levels (10.9Â±1.69%) of Ki-67-positive proliferating cells compared with those from DMH-treated wild-type mice (7.77Â±1.15%) (mean+SD, P<0.01) and a mild increase in apoptotic nuclei staining for cleaved caspase-3 (1.94+0.51% compared with 1.15Â±0.34%, mean+SD, P<0.01). In the adenomas from DMH-treated K-rasVal12 mice, K-rasVal12 transgene recombination and expression were confirmed and shown to promote strong Erk and mild Akt activation compared with adenomas from DMH-treated wild-type mice. Microarray hybridization and cluster analysis demonstrated different expression profiles in adenomas from DMH-treated wild-type and DMH-treated K-rasVal12 mice, indicating involvement of different molecular mechanisms, but array-comparative genomic hybridisation analysis showed chromosome stability in both, with very few chromosome alterations observed in adenomas from either of the two groups. Taken together, these data show that mutant K-ras promotes DMH-induced colorectal tumourigenesis, conferring a proliferative effect, but does not alter chromosome stability in the tumours. This study has 7 samples analysed, 4 Kras mutants and 3 controls, on the Illumina Mouse-6 Beadchip array.