Emergence of a high-plasticity cell state during lung cancer evolution, ATACseq

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profiled single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from atypical adenomatous hyperplasia to adenocarcinoma. The diversity of transcriptional states increased over time and was reproducible across tumors and mice. Cancer cells progressively adopted alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts displayed high capacity for differentiation and proliferation. The HPCS program was associated with poor survival across human cancers and demonstrated chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS. Bulk ATACseq of mouse lung tumor cells sorted by expression of Tigit.