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Functional characterisation of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer
Catozzi, Alessia Peiris-Pagès, Maria Humphrey, Sam Revill, Mitchell Morgan, Derrick Roebuck, Jordan Chen, Yitao Davies-Williams, Bethan Lallo, Alice Galvin, Melanie
Catozzi, Alessia
Peiris-Pagès, Maria
Humphrey, Sam
Revill, Mitchell
Morgan, Derrick
Roebuck, Jordan
Chen, Yitao
Davies-Williams, Bethan
Lallo, Alice
Galvin, Melanie
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Abstract
Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ASCL1, NEUROD1, POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC Circulating tumour cell-Derived eXplant (CDX) model biobank. Here we show that ATOH1 protein was detected in 7/81 preclinical models and 16/102 clinical samples of SCLC. In CDX models, ATOH1 directly regulated neurogenesis and differentiation programs consistent with roles in normal tissues. In ex vivo cultures of ATOH1-positive CDX, ATOH1 was required for cell survival. In vivo, ATOH1 depletion slowed tumour growth and suppressed liver metastasis. Our data validate ATOH1 as a bona fide oncogenic driver of SCLC with tumour cell survival and pro-metastatic functions. Further investigation to explore ATOH1 driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.
Authors
Catozzi, Alessia
Peiris-Pagès, Maria
Humphrey, Sam
Revill, Mitchell
Morgan, Derrick
Roebuck, Jordan
Chen, Yitao
Davies-Williams, Bethan
Lallo, Alice
Galvin, Melanie
Pearce, Simon P
Kerr, Alastair
Priest, Lynsey
Foy, Victoria
Carter, Mathew
Caeser, R.
Chan, J.
Rudin, C. M.
Blackhall, Fiona
Frese, Kristopher K
Dive, Caroline
Simpson, Kathryn L
Peiris-Pagès, Maria
Humphrey, Sam
Revill, Mitchell
Morgan, Derrick
Roebuck, Jordan
Chen, Yitao
Davies-Williams, Bethan
Lallo, Alice
Galvin, Melanie
Pearce, Simon P
Kerr, Alastair
Priest, Lynsey
Foy, Victoria
Carter, Mathew
Caeser, R.
Chan, J.
Rudin, C. M.
Blackhall, Fiona
Frese, Kristopher K
Dive, Caroline
Simpson, Kathryn L
Description
Date
2024
Publisher
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Keywords
Type
Preprint
Citation
Catozzi A, Peiris-Pagès M, Humphrey S, Revill M, Morgan D, Roebuck J, et al. Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer. bioRxiv : the preprint server for biology. 2024 Feb 17. PubMed PMID: 38405859. Pubmed Central PMCID: PMC10888785. Epub 2024/02/26. eng.