Tumor microenvironment landscapes supporting EGFR-mutant NSCLC are modulated at the single cell interaction level by Unesbulin treatment
Lung cancer is the leading cause of cancer deaths. Lethal pulmonary adenocarcinomas (ADCs) present with frequent mutations in the Epidermal Growth Factor Receptor (EGFR). Genetically-engineered murine models of lung cancer expedited comprehension of the molecular mechanisms driving tumorigenesis and drug response. Here, we systematically analyzed the evolution of tumor heterogeneity in the context of dynamic interactions occurring with the intermingled tumor microenvironment by high resolution transcriptomics. Our effort identified vulnerable tumor-specific epithelial cells, as well as their cross-talk with niche components (endothelial cells, fibroblasts and tumor-infiltrating immune cells), whose symbiotic interface shapes tumor aggressiveness and is almost completely abolished by treatment with Unesbulin, a tubulin binding agent that reduces BMI-1 activity. Simultaneous MRI analysis demonstrated decreased tumor growth, setting the stage for future investigations into the potential of novel therapeutic strategies for EGFR-mutant ADCs. Overall design: Single cell RNA sequencing (scRNAseq) of lung tissues from EGFR-mutant model mice using InDrops-seq. The dataset includes five samples, each sequenced with distinct index sequences. Upon demultiplexing with these indexes, the dataset includes a total of 17 samples, comprising 2 untreated healthy samples, 2 healthy samples treated with a vehicle, 2 healthy samples treated with Unesbulin, 8 tumor samples treated with a vehicle, and 3 tumor samples treated with Unesbulin.