Anke Koeniger, Pierfrancesco Polo, Anna Brichkina, Florian Finkernagel, Alexander Visekruna, Andrea Nist, Thorsten Stiewe, Michael Daude, Wibke E Diederich, Thomas M Gress, Till Adhikary, Matthias Lauth
{"title":"通过小分子治疗破坏与癌症亚型相关的超级增强子回路,从而抑制肿瘤。","authors":"Anke Koeniger, Pierfrancesco Polo, Anna Brichkina, Florian Finkernagel, Alexander Visekruna, Andrea Nist, Thorsten Stiewe, Michael Daude, Wibke E Diederich, Thomas M Gress, Till Adhikary, Matthias Lauth","doi":"10.1093/narcan/zcad007","DOIUrl":null,"url":null,"abstract":"<p><p>Transcriptional cancer subtypes which correlate with traits such as tumor growth, drug sensitivity or the chances of relapse and metastasis, have been described for several malignancies. The core regulatory circuits (CRCs) defining these subtypes are established by chromatin super enhancers (SEs) driving key transcription factors (TFs) specific for the particular cell state. In neuroblastoma (NB), one of the most frequent solid pediatric cancer entities, two major SE-directed molecular subtypes have been described: A more lineage-committed adrenergic (ADRN) and a mesenchymal (MES) subtype. Here, we found that a small isoxazole molecule (ISX), a frequently used pro-neural drug, reprogrammed SE activity and switched NB cells from an ADRN subtype towards a growth-retarded MES-like state. The MES-like state shared strong transcriptional overlap with ganglioneuroma (GN), a benign and highly differentiated tumor of the neural crest. Mechanistically, ISX suppressed chromatin binding of N-MYC, a CRC-amplifying transcription factor, resulting in loss of key ADRN subtype-enriched components such as N-MYC itself, PHOX2B and ALK, while concomitently, MES subtype markers were induced. Globally, ISX treatment installed a chromatin accessibility landscape typically associated with low risk NB. In summary, we provide evidence that CRCs and cancer subtype reprogramming might be amenable to future therapeutic targeting.</p>","PeriodicalId":18879,"journal":{"name":"NAR Cancer","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2023-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900422/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tumor-suppressive disruption of cancer subtype-associated super enhancer circuits by small molecule treatment.\",\"authors\":\"Anke Koeniger, Pierfrancesco Polo, Anna Brichkina, Florian Finkernagel, Alexander Visekruna, Andrea Nist, Thorsten Stiewe, Michael Daude, Wibke E Diederich, Thomas M Gress, Till Adhikary, Matthias Lauth\",\"doi\":\"10.1093/narcan/zcad007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Transcriptional cancer subtypes which correlate with traits such as tumor growth, drug sensitivity or the chances of relapse and metastasis, have been described for several malignancies. The core regulatory circuits (CRCs) defining these subtypes are established by chromatin super enhancers (SEs) driving key transcription factors (TFs) specific for the particular cell state. In neuroblastoma (NB), one of the most frequent solid pediatric cancer entities, two major SE-directed molecular subtypes have been described: A more lineage-committed adrenergic (ADRN) and a mesenchymal (MES) subtype. Here, we found that a small isoxazole molecule (ISX), a frequently used pro-neural drug, reprogrammed SE activity and switched NB cells from an ADRN subtype towards a growth-retarded MES-like state. The MES-like state shared strong transcriptional overlap with ganglioneuroma (GN), a benign and highly differentiated tumor of the neural crest. Mechanistically, ISX suppressed chromatin binding of N-MYC, a CRC-amplifying transcription factor, resulting in loss of key ADRN subtype-enriched components such as N-MYC itself, PHOX2B and ALK, while concomitently, MES subtype markers were induced. Globally, ISX treatment installed a chromatin accessibility landscape typically associated with low risk NB. In summary, we provide evidence that CRCs and cancer subtype reprogramming might be amenable to future therapeutic targeting.</p>\",\"PeriodicalId\":18879,\"journal\":{\"name\":\"NAR Cancer\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-02-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9900422/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NAR Cancer\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/narcan/zcad007\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/3/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NAR Cancer","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/narcan/zcad007","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/3/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
一些恶性肿瘤的转录癌症亚型与肿瘤生长、药物敏感性或复发和转移几率等特征相关。定义这些亚型的核心调控回路(CRC)是由驱动特定细胞状态的关键转录因子(TF)的染色质超级增强子(SE)建立的。神经母细胞瘤(NB)是最常见的小儿实体瘤之一,目前已描述了两种主要的SE定向分子亚型:一种是线粒体肾上腺素能亚型(ADRN),另一种是间质亚型(MES)。在这里,我们发现一种常用的促神经药物--异噁唑小分子(ISX)能重编程 SE 的活性,并将 NB 细胞从 ADRN 亚型转换为生长迟缓的 MES 样态。MES样状态与神经节细胞瘤(GN)有很强的转录重叠,后者是神经嵴的一种高分化良性肿瘤。从机理上讲,ISX抑制了N-MYC(一种CRC扩增转录因子)的染色质结合,导致N-MYC本身、PHOX2B和ALK等ADRN亚型丰富的关键成分缺失,同时诱导了MES亚型标志物。从整体上看,ISX 处理设置的染色质可及性景观通常与低风险 NB 相关。总之,我们提供的证据表明,CRC 和癌症亚型重编程可能适合未来的靶向治疗。
Tumor-suppressive disruption of cancer subtype-associated super enhancer circuits by small molecule treatment.
Transcriptional cancer subtypes which correlate with traits such as tumor growth, drug sensitivity or the chances of relapse and metastasis, have been described for several malignancies. The core regulatory circuits (CRCs) defining these subtypes are established by chromatin super enhancers (SEs) driving key transcription factors (TFs) specific for the particular cell state. In neuroblastoma (NB), one of the most frequent solid pediatric cancer entities, two major SE-directed molecular subtypes have been described: A more lineage-committed adrenergic (ADRN) and a mesenchymal (MES) subtype. Here, we found that a small isoxazole molecule (ISX), a frequently used pro-neural drug, reprogrammed SE activity and switched NB cells from an ADRN subtype towards a growth-retarded MES-like state. The MES-like state shared strong transcriptional overlap with ganglioneuroma (GN), a benign and highly differentiated tumor of the neural crest. Mechanistically, ISX suppressed chromatin binding of N-MYC, a CRC-amplifying transcription factor, resulting in loss of key ADRN subtype-enriched components such as N-MYC itself, PHOX2B and ALK, while concomitently, MES subtype markers were induced. Globally, ISX treatment installed a chromatin accessibility landscape typically associated with low risk NB. In summary, we provide evidence that CRCs and cancer subtype reprogramming might be amenable to future therapeutic targeting.