Cell reports · 2025
Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer.
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Catozzi Alessia, Peiris Pagès Maria, Humphrey Sam, Revill Mitchell, Morgan Derrick, Roebuck Jordan, Chen Yitao, Davies-Williams Bethan, Brennan Kevin, Mukarram Hossain A S Md, Makeev Vsevolod J, Satia Karishma, Sfyri Pagona P, Galvin Melanie, Coles Darryl, Lallo Alice, Pearce Simon P, Kerr Alastair, Priest Lynsey, Foy Victoria, Carter Mathew, Caeser Rebecca, Chan Joseph M, Rudin Charles M, Blackhall Fiona, Frese Kristopher K, Dive Caroline, Simpson Kathryn L
Аннотация
Molecular subtypes of small cell lung cancer (SCLC) have been described based on differential expression of the transcription factors (TFs) ASCL1, NEUROD1, and POU2F3 and immune-related genes. We previously reported 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, ATOH1 is required for 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 pro-metastatic functions. Further investigation exploring ATOH1-driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.