Abstract 6626: Functional and molecular interrogation of a high-plasticity cell state in lung cancer

Abstract Despite recent advancements in lung adenocarcinoma (LUAD) treatment, mortality remains high. Thus, a need exists for novel therapeutic concepts to enhance treatment efficacy and improve patient survival. Cancer cell plasticity, the capacity for cancer cells to differentiate and adapt to cell-extrinsic pressures, drives LUAD progression and enables treatment resistance. We discovered a molecularly distinct "high-plasticity cell state" (HPCS), which emerges during the initial stages of tumor development and is maintained in established tumors, comprising 10-15% of the cancer cell pool. We hypothesized that the HPCS is critical for tumor progression and drug resistance. To functionally interrogate this cell state, we engineered a novel genetic system that enables both in situ ablation (via a suicide gene) and longitudinal lineage tracing (via secreted luciferases) of the HPCS in an autochthonous genetically engineered mouse LUAD model. Lineage-tracing revealed the HPCS harbors high differentiation potential (plasticity) and growth potential in situ. Strikingly, ablation of the HPCS led to robust tumor regression and growth suppression. Motivated by these findings, we sought to identify molecular drivers of the HPCS using an in vivo multiplexed gene perturbation approach coupled to single-cell RNA sequencing. This effort led to the identification of central transcriptional plasticity drivers. This study motivates the therapeutic targeting of the HPCS in lung cancer and uncovers candidate targets. Citation Format: Jason Earl Chan, Chun-Hao Pan, Carleigh Sussman, Hannah Styers, Emma Brown, Griffin Hartmann, Brigita Meškauskaitė, Melissa Blum, Selena Ding, Stefan Torborg, Zhuxuan Li, Simon Joost, Eliud Rivas-Hernandez, Thomas Norman, Ronan Chaligne, Yan Yan, Tuomas Tammela. Functional and molecular interrogation of a high-plasticity cell state in lung cancer 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 6626.