Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma,Cancer Discovery

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Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma
Cancer Discovery ( IF 29.7 ) Pub Date : 2018-05-01 , DOI: 10.1158/2159-8290.cd-16-0861
Presha Rajbhandari _{1,

2} , Gonzalo Lopez _{1,

3} , Claudia Capdevila ₁ , Beatrice Salvatori ₁ , Jiyang Yu _{1,

4} , Ruth Rodriguez-Barrueco _{5,

6} , Daniel Martinez ₃ , Mark Yarmarkovich ₃ , Nina Weichert-Leahey ₇ , Brian J Abraham ₈ , Mariano J Alvarez ₁ , Archana Iyer ₁ , Jo Lynne Harenza ₃ , Derek Oldridge ₃ , Katleen De Preter ₉ , Jan Koster ₁₀ , Shahab Asgharzadeh _{11,

12} , Robert C Seeger _{11,

12} , Jun S Wei ₁₃ , Javed Khan ₁₃ , Jo Vandesompele ₉ , Pieter Mestdagh ₉ , Rogier Versteeg ₁₀ , A Thomas Look ₇ , Richard A Young _{8,

14} , Antonio Iavarone ₁₅ , Anna Lasorella ₁₆ , Jose M Silva ₅ , John M Maris _{3,

17,

18} , Andrea Califano _{1,

19,

20,

21}

Affiliation

Department of Systems Biology, Columbia University, New York, New York.
Department of Biological Sciences, Columbia University, New York, New York.
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York.
Departament de Patologia i Terapèutica Experimental, Facultat de Medicina i Ciències de la Salut, IDIBELL, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
Center for Medical Genetics & Cancer Research Institute Ghent (CRIG), Ghent University, Gent, Belgium.
Department of Oncogenomics, Academic Medical Center, Amsterdam, the Netherlands.
Division of Hematology/Oncology, Saban Research Institute, The Children's Hospital Los Angeles, Los Angeles, California.
Keck School of Medicine, University of Southern California, Los Angeles, California.
Genetics Branch, Oncogenomics Section, Center for Cancer Research, NIH, Bethesda, Maryland.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Department of Neurology and Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, New York.
Department of Pediatrics and Pathology and Cell Biology, Institute for Cancer Genetics, Columbia University, New York, New York.
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania.
Department of Biomedical Informatics, Columbia University, New York, New York.
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York.
Herbert Irving Comprehensive Cancer Center and J.P. Sulzberger Columbia Genome Center, Columbia University, New York, New York.

High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module—centered around a TEAD4–MYCN positive feedback loop—emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCN^Amp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.

Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4–MYCN positive feedback loop in MYCN^Amp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582–99. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517

中文翻译：

跨队列分析确定 TEAD4-MYCN 正反馈环是高风险神经母细胞瘤的核心调节元件

高风险神经母细胞瘤在诊断时显示出很少的复发性体细胞突变。因此，这种攻击性表型的分子基础仍然难以捉摸。调控网络分析的最新进展帮助我们阐明了基因组改变下游的疾病驱动机制，包括反复出现的染色体改变。我们的分析确定了高风险神经母细胞瘤的三种分子亚型，与染色体改变一致，并确定了在独立队列中保守的亚型特异性主调节蛋白。一个以 TEAD4-MYCN 正反馈环为中心的 10 蛋白转录模块作为与MYCN扩增相关的高风险亚型的调节驱动因素出现。任一基因的沉默都会破坏MYCN扩增 ( MYCN ^Amp ) 神经母细胞瘤的转录特征，并消除体外和体内的活力。一致地，TEAD4 成为生存不良的强有力的预后标志物，其活性独立于典型的 Hippo 通路转录共激活因子 YAP 和 TAZ。这些结果为大部分 MYCN 失调的神经母细胞瘤提出了新的治疗策略。

意义：尽管对神经母细胞瘤遗传学的理解取得了进展，但个性化治疗方面却进展甚微。在这里，我们提出了一个框架来确定维持神经母细胞瘤亚型的遗传改变的下游效应器，该框架可以很容易地扩展到其他肿瘤类型。我们展示了破坏MYCN ^Amp神经母细胞瘤中以不依赖 YAP/TAZ 的 TEAD4-MYCN 正反馈环为中心的 10 蛋白模块的关键作用，提名 TEAD4 作为治疗干预的新候选者。癌症发现； 8(5)； 582–99。 ©2018 AACR。

本文在本期专题第 12 页中重点介绍。第517章

更新日期：2018-05-01

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