Friday, May 9, 2025
5/9/2025
Targeting plasticity in lung cancer - SUMMARY Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, results in ~55,000 deaths in the US every year. Despite the recent advancements in LUAD treatment, the disease remains highly intractable. Thus, a critical unmet clinical need exists for novel and effective therapeutic strategies for LUAD patients. Cancer cell plasticity – the capacity to differentiate and adapt to cell-extrinsic pressure – drives tumor progression and is a major cause of treatment failure in LUAD. Thus, targeting plasticity in LUAD is a promising therapeutic concept. Realizing the therapeutic potential of targeting cancer cell plasticity requires fundamental understanding of the cell states that promote plasticity in LUAD as well as the molecular mechanisms that drive them. Using a genetically engineered mouse model (GEMM) of LUAD and single-cell mRNA sequencing (scRNA-Seq) to investigate LUAD evolution we identified a high-plasticity cell state (HPCS) that is acquired by a subset of LUAD cells in early stages of tumor evolution. The HPCS was ubiquitously maintained in mouse and human LUAD in vivo irrespective of stage and considerable intra- and inter-tumoral genetic and phenotypic diversity. Further, the HPCS gene expression signature correlated with particularly poor patient outcomes. Prospectively isolated HPCS cells were endowed with robust capacity for differentiation (plasticity) and proliferation, and the HPCS was strongly enriched following chemotherapy. Our preliminary work strongly supports plasticity is concentrated in the HPCS and that it is associated with high growth potential and chemoresistance. However, the contribution or essentiality of the HPCS for LUAD growth, treatment resistance, or emergence of new malignant cell states within LUAD tumors is not known. Similarly, little is known of the transcriptional drivers of LUAD plasticity. We hypothesize that the HPCS is essential for progression of premalignant neoplasias to LUAD as well as for LUAD growth, cell state transitions, and chemoresistance. To address this hypothesis, we will interrogate HPCS in LUAD progression and treatment resistance using lineage- ablation and lineage-tracing using a novel reporter system that we have generated, which we will combine with scRNA-seq. To address molecular HPCS drivers, we will inactivate or overexpress two candidate transcription factors in the LUAD GEMM and in human patient-derived xenograft (PDX) LUAD models, followed by gene expression and chromatin accessibility profiling. Our proposed study will allow us to establish the HPCS, a previously unknown cell state, as key to eradicating plasticity in LUAD. This would lead to a new treatment paradigm, motivating targeting of high-plasticity cell states across solid tumors. Furthermore, our work will contribute a novel platform for the in situ investigation of cell state heterogeneity in cancers in vivo.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).