Abstract 6935: Non-genetic routes of lung cancer evolution

Abstract Cancer cell plasticity underlies the progression of several solid tumors. In lung adenocarcinoma, morphological changes characterizing the transition from indolent to aggressive disease exhibit profound epigenetic and transcriptional reprogramming1. However, the extent, features, and drivers of cancer cell plasticity in the progression of human lung adenocarcinoma is still largely unexplored. Here, we assembled and analyzed a meta-cohort of 119 human lung tumors analyzed by single-cell RNA-sequencing, for a total of ~730, 000 cells. Cancer cell heterogeneity was the result of differential activation of 17 transcriptional programs associated with common cancer phenotypes, such as proliferation, cell migration, and response to hypoxia, as well as alveolar lineage identity (AT2). In particular, AT2-specific expression of MHC-II was down-regulated with the progression of the disease and markedly reduced in KEAP1 and/or STK11 mutated samples, providing a rationale for the association between these mutations and immunotherapy resistance. Co-activation of transcriptional programs clustered tumor cells in 4 major cell states, which emerged with the progression of the disease. To explore spatial distribution of different cancer cell states, we generated and analyzed multiple spatial transcriptomics and proteomics lung adenocarcinoma cohorts. To this purpose we developed a new algorithm called CellCharter2. CellCharter identified distinct cancer-enriched niches within individual samples, corresponding to the cancer cell states that we discovered in the scRNA-seq cohort and exhibited specific interactions with the tumor microenvironment (TME). In particular, we identified a cancer cell state characterized by response-to-hypoxia and migratory phenotypes, which spatially segregated from highly proliferative cancer cell niches and formed specific interactions with tumor associated neutrophils. This cell state was enriched in advanced primary samples, it uniquely characterized metastatic samples, and was an independent marker of poor prognosis across multiple independent datasets. Overall, our work uncovered cell plasticity trajectories associated with the progression of lung adenocarcinoma and shed new light into the tumor-TME interactions at their origin. 1 Tavernari et al. , Cancer Discovery, 20212 Varrone et al, Nat. Genetics, (in press) Citation Format: Giovanni Ciriello, Daniele Tavernari, Marco Varrone. Non-genetic routes of lung cancer evolution 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 6935.