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EIF6 conditions drug-tolerant persister-like transdifferentiation in small cell lung carcinoma (SCLC cell lines)

ABSTRACT: Drug-tolerant persister cells withstand treatments by adapting their identity through lineage-dependent plasticity during systemic anti-cancer therapies. This phenomenon is evident in small-cell lung carcinoma (SCLC), a lethal neuroendocrine cancer initially responsive (60-80%) to platinum-based chemotherapy but succumbing to resistance within 6 months in advanced stages. This resistance associates with the transdifferentiation of residual tumour cells into a non-neuroendocrine state, a process intricately tied to SCLC's chemotolerance, yet molecular mechanisms governing this lineage conversion remain completed understood. Here we use paired cytoplasmic RNA-seq and polysomal RNA-seq to compare gene expression between NE and non-NE SCLC cell lines on both transcriptional and translational level. We report that first-line chemotherapy induces translation initiation factor eIF6 in drug-tolerant persister-like cells in SCLC, correlating with the non-neuroendocrine state in SCLC. Intervening eIF6 inhibits non-neuroendocrine transdifferentiation, thus enhancing SCLC responsiveness to chemotherapy. This study sheds light on eIF6's potential therapeutic interventions to mitigate treatment resistance in SCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262593 | GEO | 2024/04/30

REPOSITORIES: GEO

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EIF6 conditions drug-tolerant persister-like transdifferentiation in small cell lung carcinoma (eIF6_KD)

Project description:Drug-tolerant persister cells withstand treatments by adapting their identity through lineage-dependent plasticity during systemic anti-cancer therapies. This phenomenon is evident in small-cell lung carcinoma (SCLC), a lethal neuroendocrine cancer initially responsive (60-80%) to platinum-based chemotherapy but succumbing to resistance within 6 months in advanced stages. This resistance associates with the transdifferentiation of residual tumour cells into a non-neuroendocrine state, a process intricately tied to SCLC's chemotolerance, yet molecular mechanisms governing this lineage conversion remain completed understood. Here we use paired cytoplasmic RNA-seq and polysomal RNA-seq to compare gene expression between NE and non-NE SCLC cell lines on both transcriptional and translational level. We report that first-line chemotherapy induces translation initiation factor eIF6 in drug-tolerant persister-like cells in SCLC, correlating with the non-neuroendocrine state in SCLC. Intervening eIF6 inhibits non-neuroendocrine transdifferentiation, thus enhancing SCLC responsiveness to chemotherapy. This study sheds light on eIF6's potential therapeutic interventions to mitigate treatment resistance in SCLC.

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