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Molecular subtypes of small cell lung cancer (SCLC) have been described based on differential expression of the transcription factors (TFs) ASCL1,NEUROD1,andPOU2F3andimmune-relatedgenes.Wepreviouslyreported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC circulating tumor cell-derived explant (CDX) model biobank. Here, we show that ATOH1 protein is detected in 7 of 81 preclinical models and 16 of 102 clinical samples of SCLC. In CDX models, ATOH1 directly regulates neurogenesis and differentiation programs, consistent with roles in normal tissues. In ex vivo cultures of ATOH1+ CDXs,ATOH1isrequiredfor cell survival. In vivo, ATOH1 depletion slows tumor growth and suppresses liver metastasis. Our data validate ATOH1 as a bona fide lineage-defining TF of SCLC with cell survival and prometastaticfunctions.FurtherinvestigationexploringATOH1-drivenvulnerabilitiesfortargetedtreatmentwith predictive biomarkers is warranted.
Molecular subtypes of small cell lung cancer (SCLC) have been described based on differential expression of the transcription factors (TFs) ASCL1,NEUROD1,andPOU2F3andimmune-relatedgenes.Wepreviouslyreported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC circulating tumor cell-derived explant (CDX) model biobank. Here, we show that ATOH1 protein is detected in 7 of 81 preclinical models and 16 of 102 clinical samples of SCLC. In CDX models, ATOH1 directly regulates neurogenesis and differentiation programs, consistent with roles in normal tissues. In ex vivo cultures of ATOH1+ CDXs,ATOH1isrequiredfor cell survival. In vivo, ATOH1 depletion slows tumor growth and suppresses liver metastasis. Our data validate ATOH1 as a bona fide lineage-defining TF of SCLC with cell survival and prometastaticfunctions.FurtherinvestigationexploringATOH1-drivenvulnerabilitiesfortargetedtreatmentwith predictive biomarkers is warranted.