Abstract 5394: Transcriptional reprogramming, metabolic rewiring and tumor immune microenvironment (TIME) reconfiguration: investigating the molecular underpinnings of GRAMD2+AT1 cell-derived murine LUAD

Abstract Arising from the distal alveolar epithelium, lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC), accounting for approximately 40% of lung cancer cases. The distal lung houses a variety of cell populations in addition to alveolar epithelial type 1 (AT1) and type 2 (AT2) cells. The large, squamous-appearing AT1 cells facilitate gas exchange across the air blood barrier, while their smaller, cuboidal AT2 cell counterparts synthesize and secrete pulmonary surfactants to prevent alveolar collapse. It was previously believed that AT1 cells were terminally differentiated and devoid of tumorigenic properties, while AT2 cells that are capable of both self-renewal and differentiation to AT1 cells were designated as the primary cell of origin of LUAD. Our laboratory previously demonstrated that GRAMD2+ AT1 cells could serve as a cell of origin for KRAS-mediated murine LUAD (Yang M. et al., 2023). In the current study, we investigated the functional roles of AT1 cells in EGFR-mediated LUAD tumorigenesis. We performed a longitudinal analysis spanning approximately 15 weeks where H&E-stained mouse lung tissues underwent a double blinded pathology review. We then employed spatial transcriptomic analysis to examine tumor cell composition, and the molecular underpinnings involved in cell of origin specific LUAD tumorigenesis at 5-, 10-, and 15-weeks post-activation of oncogenic transformation. Our findings illustrate that AT1 cell-derived LUAD undergoes significant transcriptional reprogramming, metabolic rewiring, and tumor immune microenvironment (TIME) reconfiguration over time. Our analysis revealed that Gramd2+ AT1 cell-derived tumors at 5 weeks exhibited a bioenergetic reliance upon mitochondrial OXPHOS, while AT1 cell derived LUAD tumors at 15 weeks exhibited metabolic flexibility as they underwent a glycolytic switch. As this metabolic rewiring and transcriptional reprogramming occurred, TIME reconfiguration also took place. At 5 weeks, tumors exhibited a robust anti-tumor immune response and infiltration, which declined by 15 weeks post tamoxifen administration. Furthermore, at 5 weeks there was significant extracellular matrix (ECM) remodeling and stromal promotion of angiogenesis (e.g. Vegfa, and Tgfb). This transcriptional reprogramming and metabolic rewiring may facilitate the observed progressive murine LUAD malignancy that occurs overtime. These findings provide key insights into the interchange between AT1 cell derived LUAD tumors and their TIME revealing potential metabolic vulnerabilities and targetable transcriptional events. Citation Format: Angel P. Hunt, Aaron Neely, Andrea Lanz, MauriAnna Richardson, Benecia Jackson, Zea Borok, Crystal N. Marconett. Transcriptional reprogramming, metabolic rewiring and tumor immune microenvironment (TIME) reconfiguration: investigating the molecular underpinnings of GRAMD2+AT1 cell-derived murine LUAD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5394.