Transcriptional networks underlying tumour plasticity in small-cell lung cancer

ABSTRACT: Across human malignancies, the ability of cancer cells to switch between different states (“plasticity”) contributes to tumour progression, metastasis, and resistance to therapy . Here we investigated the transcriptional and epigenetic basis of plasticity in small-cell lung cancer (SCLC), a cancer type that grows aggressively and is notoriously recalcitrant to therapy . SCLC tumours display heterogeneity along a neuroendocrine (NE) to nonNE axis, but the factors regulating these differentiation states and inter-state transition remains poorly defined 6. Using single-cell multi-omics, we identified distinct transcriptional SCLC cell states, including a previously unrecognized Intermediate state comprised of immunogenic SCLC cells with bipotent NE/nonNE differentiation potential. Additionally, developing a Boolean Bayes model for transcription factor networks (BoBa-T) allowed us to predict regulators of SCLC cell states. We validated RORB as a transcription factor that promotes the NE state and represses the nonNE state in SCLC. Notably, RORB inactivation promotes the transition of NE SCLC cells to the Intermediate state, including upregulation of immunogenic programs, leading to inhibition of tumour growth. Our work identifies a highly plastic state in SCLC tumours and reveals new strategies to limit plasticity and heterogeneity enhancing the efficacy of therapies in this fatal form of human cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE325242 | GEO | 2026/09/30

REPOSITORIES: GEO