Cytosolic DNA sensor AIM2 promotes KRAS-driven lung cancer independent of inflammasomes.

Autor: Alanazi M; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia., Weng T; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia., McLeod L; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia., Gearing LJ; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia., Smith JA; Department of Surgery, School of Clinical Sciences/Monash Health, Monash University, Clayton, Victoria, Australia., Kumar B; Department of Anatomical Pathology, Monash Health, Clayton, Victoria, Australia., Saad MI; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia., Jenkins BJ; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.; South Australian immunoGENomics Cancer Institute (SAiGENCI), The University of Adelaide, Adelaide, South Australia, Australia.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2024 Jun; Vol. 115 (6), pp. 1834-1850. Date of Electronic Publication: 2024 Apr 09.
DOI: 10.1111/cas.16171
Abstrakt: 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-1β 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.
(© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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