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

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-04-29 DOI:10.1016/j.celrep.2025.115603

Alessia Catozzi, Maria Peiris Pagès, Sam Humphrey, Mitchell Revill, Derrick Morgan, Jordan Roebuck, Yitao Chen, Bethan Davies-Williams, Kevin Brennan, A S Md Mukarram Hossain, Vsevolod J Makeev, Karishma Satia, Pagona P Sfyri, Melanie Galvin, Darryl Coles, Alice Lallo, Simon P Pearce, Alastair Kerr, Lynsey Priest, Victoria Foy, Mathew Carter, Rebecca Caeser, Joseph M Chan, Charles M Rudin, Fiona Blackhall, Kristopher K Frese, Caroline Dive, Kathryn L Simpson

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引用次数: 0

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.

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ATOH1分子亚型的功能特征表明在小细胞肺癌中具有促转移作用。

基于转录因子（TFs） ASCL1、NEUROD1和POU2F3和免疫相关基因的差异表达，已经描述了小细胞肺癌（SCLC）的分子亚型。我们之前在我们的SCLC循环肿瘤细胞源性外植体（CDX）模型生物库中报道了基于神经源性TF ATOH1表达的另一个亚型。在这里，我们发现ATOH1蛋白在81个临床前模型中的7个和102个SCLC临床样本中的16个中检测到。在CDX模型中，ATOH1直接调节神经发生和分化程序，与正常组织中的作用一致。在体外培养的ATOH1+ cdx中，ATOH1是细胞存活所必需的。在体内，ATOH1缺失减缓肿瘤生长并抑制肝转移。我们的数据验证了ATOH1是SCLC中具有细胞存活和促转移功能的真正的谱系定义TF。有必要进一步研究atoh1驱动的脆弱性，以便用预测性生物标志物进行靶向治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.