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Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer

Catozzi, A.
; 
Peiris Pagès, M.
; 
Humphrey, S.
; 
Revill, M.
; 
Morgan, D.
; 
Roebuck, J.
; 
Chen, Y.
; 
Davies-Williams, B.
; 
Brennan, K.
; 
Mukarram Hossain, A. S. M.
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Abstract
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.
Authors
Catozzi, A.
Peiris Pagès, M.
Humphrey, S.
Revill, M.
Morgan, D.
Roebuck, J.
Chen, Y.
Davies-Williams, B.
Brennan, K.
Mukarram Hossain, A. S. M.
Makeev, V. J.
Satia, K.
Sfyri, P. P.
Galvin, M.
Coles, D.
Lallo, A.
Pearce, S. P.
Kerr, A.
Priest, L.
Foy, V.
Carter, M.
Caeser, R.
Chan, J. M.
Rudin, C. M.
Blackhall, F.
Frese, K. K.
Dive, C.
Simpson, K. L.
Affiliation
SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK. Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK. Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK. Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M20 4BX, UK. SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK. SCLC Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK; Cancer Research UK Lung Cancer Centre of Excellence, Manchester and London, UK; Cancer Research UK National Biomarker Centre, University of Manchester, Manchester M20 4BX, UK. Electronic address: caroline.dive@cruk.manchester.ac.uk.
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2025
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All Christie Publications
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Catozzi A, Peiris Pagès M, Humphrey S, Revill M, Morgan D, Roebuck J, et al. Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer. Cell reports. 2025 May 27;44(5):115603. PubMed PMID: 40305287. Pubmed Central PMCID: PMC12116416. Epub 2025/04/30. eng.
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https://christie.openrepository.com/handle/10541/627765
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