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

   

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.
Article Title:	Functional characterization of the ATOH1 molecular subtype indicates a pro-metastatic role in small cell lung cancer
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. © 2025 The Authors
Keywords:	immunohistochemistry; controlled study; protein expression; unclassified drug; human cell; cisplatin; nonhuman; flow cytometry; biological marker; animal tissue; cell viability; cell survival; metastasis; apoptosis; gene expression; etoposide; animal experiment; animal model; protein; transcription factor; cell differentiation; explant; transcriptomics; liver metastasis; chromatin immunoprecipitation; western blotting; nervous system development; fluorescence activated cell sorting; small cell lung cancer; sclc; principal component analysis; gene ontology; transcription factor mash1; pyroptosis; ferroptosis; human; female; article; differential gene expression; whole exome sequencing; gene set enrichment analysis; neurogenic differentiation factor; single cell rna seq; ht-29 cell line; atoh1; cp: cancer; atonal bhlh transcription factor 1; cdx; ctc-derived explant models; sclc molecular subtype; pou class 2 homeobox 3; tumor cell derived explant
Journal Title:	Cell Reports
Volume:	44
Issue:	5
ISSN:	2211-1247
Publisher:	Cell Press
Date Published:	2025-05-27
Start Page:	115603
Language:	English
DOI:	10.1016/j.celrep.2025.115603
PROVIDER:	scopus
PMCID:	PMC12116416
PUBMED:	40305287
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105003977785&doi=10.1016%2fj.celrep.2025.115603&partnerID=40&md5=21dddf0e4a14a028fd371631d71092e4
Notes:	Article -- Source: Scopus

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