Lung cancer is the most lethal of all cancer types, and a major genetic driver for lung cancer are oncogenic KRAS mutations. To date, the development of targeted KRAS therapies for clinical implementation has been unsuccessful, and thus there is an urgent need for alternative approaches to target and block oncogenic KRAS signaling pathways. AIM2 is a DNA sensor of innate immunity, and has also been shown to form “inflammasome” complexes that control production of mature cytokines, IL-1b and IL-18. In cancer, AIM2 is differentially expressed among certain cancer types. For instance, AIM2 low expression has been associated with poor prognosis in colorectal cancer. However, AIM2 high expression has been implicated in the progression of oral squamous cell carcinoma. In human lung adenocarcinoma (LAC), AIM2 was over expressed compared with other DNA sensors and inflammasome components, so we investigated the role of AIM2 in the pathogenesis of LAC.
Genetic (KrasLSL-G12D/+) and carcinogen (NNK)-induced mouse models of LAC were coupled with Aim2-/- mice. Oncogenic KrasG12D was activated using intranasal inhalation of Adenovirus Cre recombinase, while NNK (100mg/kg) was injected intraperitoneally into Aim2-/- mice on the tumour-sensitive A/J background. Aim2 mRNA levels were elevated in the lungs of both models, whereas other DNA sensors and inflammasome components were not.
Aim2 deficient mice in both KrasG12Dand NNK-induced LAC models had a decreased tumour burden. Consistent with this tumour burden decrease, immunohistochemistry (IHC) revealed a reduction in staining for the adenocarcinoma marker, TTF-1, and the proliferation marker, PCNA, compared to WT mice. Interestingly, IHC staining for the inflammation marker, CD45, showed no significant change in Aim2-/- mice. With respect to inflammasome activation, levels of caspase-1 were unaltered in both models, suggesting that AIM2 may play an independent role from the inflammasome in LAC.
Altogether, our data suggest that AIM2 plays a significant role in KRAS-driven LAC formation. In addition, AIM2 might act independently from the inflammasome.