| First Author | Alanazi M | Year | 2024 |
| Journal | Cancer Sci | Volume | 115 |
| Issue | 6 | Pages | 1834-1850 |
| PubMed ID | 38594840 | Mgi Jnum | J:349090 |
| Mgi Id | MGI:7646127 | Doi | 10.1111/cas.16171 |
| Citation | Alanazi M, et al. (2024) Cytosolic DNA sensor AIM2 promotes KRAS-driven lung cancer independent of inflammasomes. Cancer Sci 115(6):1834-1850 |
| abstractText | Constitutively active KRAS mutations are among the major drivers of lung cancer, yet the identity of molecular co-operators of oncogenic KRAS in the lung remains ill-defined. The innate immune cytosolic DNA sensor and pattern recognition receptor (PRR) Absent-in-melanoma 2 (AIM2) is best known for its assembly of multiprotein inflammasome complexes and promoting an inflammatory response. Here, we define a role for AIM2, independent of inflammasomes, in KRAS-addicted lung adenocarcinoma (LAC). In genetically defined and experimentally induced (nicotine-derived nitrosamine ketone; NNK) LAC mouse models harboring the Kras(G12D) driver mutation, AIM2 was highly upregulated compared with other cytosolic DNA sensors and inflammasome-associated PRRs. Genetic ablation of AIM2 in Kras(G12D) and NNK-induced LAC mouse models significantly reduced tumor growth, coincident with reduced cellular proliferation in the lung. Bone marrow chimeras suggest a requirement for AIM2 in Kras(G12D)-driven LAC in both hematopoietic (immune) and non-hematopoietic (epithelial) cellular compartments, which is supported by upregulated AIM2 expression in immune and epithelial cells of mutant KRAS lung tissues. Notably, protection against LAC in AIM2-deficient mice is associated with unaltered protein levels of mature Caspase-1 and IL-1beta inflammasome effectors. Moreover, genetic ablation of the key inflammasome adapter, ASC, did not suppress Kras(G12D)-driven LAC. In support of these in vivo findings, AIM2, but not mature Caspase-1, was upregulated in human LAC patient tumor biopsies. Collectively, our findings reveal that endogenous AIM2 plays a tumor-promoting role, independent of inflammasomes, in mutant KRAS-addicted LAC, and suggest innate immune DNA sensing may provide an avenue to explore new therapeutic strategies in lung cancer. |
