Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer
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
- Vsevolod J. Makeev (ORCID: https://orcid.org/0000-0001-9405-9748)
- Sam Humphrey (ORCID: https://orcid.org/0000-0003-0739-0622)
- Karishma Satia
- Joseph M. Chan (ORCID: https://orcid.org/0000-0001-5249-7395)
- Victoria Foy
- Mitchell Revill
- Alice Lallo (ORCID: https://orcid.org/0000-0001-5153-9899)
- Caroline Dive (ORCID: https://orcid.org/0000-0002-1726-8850)
- Charles M. Rudin (ORCID: https://orcid.org/0000-0001-5204-3465)
- Mireia Alemany i Pagès (ORCID: https://orcid.org/0000-0002-4419-3532)
- Pagona Panagiota Sfyri
- Alessia Catozzi (ORCID: https://orcid.org/0000-0002-7263-5203)
- Simon P. Pearce (ORCID: https://orcid.org/0000-0002-1680-5538)
- Jordan Roebuck
- Mathew Carter
- Kathryn Simpson (ORCID: https://orcid.org/0000-0002-4386-0401)
- Alastair Kerr (ORCID: https://orcid.org/0000-0001-9207-6050)
- Rebecca Caeser (ORCID: https://orcid.org/0000-0002-8416-9844)
- Lynsey Priest (ORCID: https://orcid.org/0000-0003-3780-8508)
- David M. Coles
- Fiona Helen Blackhall (ORCID: https://orcid.org/0000-0001-8716-3395)
- Bethan Davies-Williams
- Yitao Chen
- A. S. Md Mukarram Hossain
- Kristopher K. Frese
- Derrick Morgan
- Kevin F. Brennan
- Melanie Galvin
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cancer Research UK (GB)
- Cancer Research UK Manchester Institute (GB)
- The Christie NHS Foundation Trust (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1016/j.celrep.2025.115603
- Citations
- 7
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 7.32