What does this research mean for the field?

Aged genetically diverse mice spontaneously develop malignant lung adenocarcinomas—contrary to traditional descriptions of them as benign adenomas—that share common spatial multiomic pathways and microenvironmental features with human lung tumors. Novelty: ClaimNovelty.CONTRADICTORY. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

The aim is to explore similarities between spontaneous lung adenocarcinomas in aged mice and human never-smoking tumors using multiomic techniques.

April 5, 2026

Abstract 1204: Spatial multiomic characterization of spontaneous lung tumors in aged mice.

Key Points

The aim is to explore similarities between spontaneous lung adenocarcinomas in aged mice and human never-smoking tumors using multiomic techniques.
Aged Diversity Outbred and UM-HET3 mice underwent necropsied to assess for tumors.
Tumor types were annotated by pathologists using H&E staining.
Tumor samples underwent analysis through Xenium spatial transcriptomics and Codex spatial proteomics.
Data were compared with TCGA RNA-seq datasets and local patient data.
Approximately 40% of aged mice developed lung lesions, with 30% identified as adenocarcinomas.
Unsupervised clustering showed common inflammatory signatures in mouse tumors.
Aggressive tumors presented higher expression of P21 protein near the stromal boundary.
Shared transcript CD2AP was significantly up-regulated in both mouse and human tumors.

Abstract

Abstract Introduction: Lung cancer is one of the most common malignancies and is the leading cause of cancer related deaths worldwide. While lung cancer incidence has decreased over time with the success of smoking and tobacco cessation campaigns, a significant burden of disease remains among non or never-smokers. Advancing age is a key risk factor for lung cancer, with incidence escalating most steeply in the fifth decade. Here we show that laboratory mice also spontaneously develop lung tumors with age. Additionally, we show that these tumors are often malignant adenocarcinomas as opposed to the adenomas traditionally described. Using spatial transcriptomic and proteomic approaches we aimed to study whether the adenocarcinomas that develop spontaneously in aged mice were similar to human never-smoking tumors. Methods: Diversity Outbred (DO) and UM-HET3 mice were housed and aged to 24 months. At 24 months, necropsies were performed on more than 600 mice, and all tissues were examined for the presence of tumors. The identified lung lesions were annotated by pathologists on hematoxylin and eosin (H 0.05). When we compared aggressive mouse tumor signatures to TCGA bulk RNA-seq signatures these patients have worse survival outcomes. CD2AP was a shared transcript significantly up-regulated in both mouse and human tumors (P 0.05). Additionally, the microenvironment of these aggressive tumors often contained p21 positive potentially senescent dendritic cells, which colocalize with T cells. Conclusion: Genetically diverse mice develop spontaneous lung adenocarcinomas that can develop into higher grade states. Multimodal analysis has revealed common pathways between spontaneously occurring mouse and human adenocarcinomas. Citation Format: Adam Thiesen, Sema Akkurt, Javad Noorbakhsh, Te-Chia Wu, Andrew Salner, Peter Yu, Susan Airhart, Olga Anczukow, Ron Korstanje, Karolina Palucka, Jeffrey H. Chuang. Spatial multiomic characterization of spontaneous lung tumors in aged mice abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1204.

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Abstract 1204: Spatial multiomic characterization of spontaneous lung tumors in aged mice.

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