Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer
Catozzi, A.; Peiris-Pages, M.; Humphrey, S.; Revill, M.; Morgan, D.; Roebuck, J.; Chen, Y.; Davies-Williams, B.; Lallo, A.; Galvin, M.; Pearce, S. P.; Kerr, A.; Priest, L.; Foy, V.; Carter, M.; Caeser, R.; Chan, J.; Rudin, C. M.; Blackhall, F.; Frese, K. K.; Dive, C.; Simpson, K. L.
Show 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.
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