Abstract 3643: Molecular pathogenesis of lung cancer associated with interstitial pneumonia

Abstract Background: Interstitial pneumonia (IP) is known to be associated with a high risk of developing lung cancer. While common mechanisms have been reported to be involved in the pathogenesis of IP and lung cancer, including genetic and epigenomic alterations or specific signaling pathway activations, many of the molecular mechanisms of lung cancer development in IP lesions remain unknown. Methods: To clarify the detailed mechanisms of the pathogenesis of lung cancer associated with IP, we performed spatially resolved transcriptomics on lung cancer specimens obtained from usual interstitial pneumonia (UIP) associated lung cancer patients. In a total of 10 patients, including five lung cancers that developed inside the UIP and five lung cancers that originated outside the UIP, regions of interest (ROIs) were selected in the tumoral tissues and their adjacent non-tumor tissues. Then, gene expression profiles were comprehensively analyzed by using GeoMx digital spatial profiler in each ROI. Results: In the UIP lesions adjacent to lung cancer, increased gene expressions associated with pulmonary fibrosis, such as COL1A1, COL3A1, and APOE, were observed, and gene set enrichment analysis (GSEA) revealed that they were associated with autoimmunity-related pathways. When we compared the tumor lesions developed inside the UIP with outside the UIP, increased gene expressions related to IP mortality were observed in the tumor cells developed inside the UIP. Interestingly, GSEA revealed that the gene set for neutrophil extracellular trap (NETs) formation was found to be upregulated in the tumor cells developed inside the UIP, suggesting that NETs plays an important role in the pathogenesis of lung cancer developed in IP lesion. Conclusions: In our study, spatially resolved transcriptomics revealed a novel pathway related to the pathogenesis of lung cancer associated with IP. Citation Format: Daisuke Mizuno, Kazuhiko Shien, Atsushi Matsuoka, Masayoshi Ohki, Shuta Tomida, Ryo Yoshichika, Tomoaki Higashihara, Fumiaki Mukohara, Naohiro Hayashi, Tomohiro Habu, Mao Yoshikawa, Ken Suzawa, Hiromasa Yamamoto, Daisuke Ennishi, Shinichi Toyooka. Molecular pathogenesis of lung cancer associated with interstitial pneumonia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3643.