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Dissecting the Pathogenesis of Ewing Sarcoma with Integrative Genomics

用综合基因组学剖析尤文肉瘤的发病机制

基本信息

批准号：
10064577
负责人：
Kimberly Stegmaier
金额：
$ 39.65万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064577
关键词：
Adolescent and Young Adult Affect Aneuploidy Architecture Attention Automobile Driving Biochemical Biological Biology Cancer Biology Cell Line Cells Child Chromatin Clinical Clinical Data Complex Data Dependence Disease Enhancers Epigenetic Process Event Ewings sarcoma Family Family member Gene Expression Genes Genetic Genetic Transcription Genomic approach Genomics Lead Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of prostate Mediating Molecular Morbidity - disease rate Mutate Mutation Neoplasm Metastasis Oncogenes Oncogenic Pathogenesis Patients Play Primary Neoplasm Publishing RNA-Binding Protein EWS Rare Diseases Recurrence Regulation Role Testing Transcription Alteration Tumor Cell Line activating transcription factor bone cancer subtypes cancer type cell type childhood sarcoma cohesin epigenetic regulation functional genomics genomic data insight loss of function member mortality next generation sequencing patient derived xenograft model promoter protein complex rare cancer transcription factor transcriptome sequencing tumor tumor initiation tumor progression tumorigenesis young adult

项目摘要

PROJECT SUMMARY Ewing sarcoma is a rare tumor that occurs in children and young adults. While Ewing sarcoma is relatively rare, the biology of this disease is also relevant to non-Ewing sarcomas, and to other cancer subtypes, due to the presence of the EWS/FLI translocation, the driving event in this disease. Similar translocations involving ETS transcription factors occur in other malignancies, including prostate cancer. Thus, understanding the biology of Ewing sarcoma may provide insight into many cancer types. We will investigate the role of secondary genetic events in the pathogenesis of Ewing sarcoma. These secondary events have been identified through next-generation sequencing of primary tumors and cell lines. Specifically, we will evaluate the role of STAG2 in mediating epigenetic and transcriptional changes induced by the driving oncogene in Ewing sarcoma, EWS/FLI. In Aim 1, we will use genomic approaches (RNAseq, ChIPseq, WGS, etc.) to assess the mechanistic role of STAG2 in the regulation of chromatin architecture, transcription, and aneuploidy in Ewing cells. In Aim 2, we will study the role of STAG2 in progression, maintenance and metastasis in Ewing sarcoma, using functional studies in Ewing sarcoma cell lines and patient-derived xenografts. In Aim 3, we will determine whether there is a synthetic lethal dependency on STAG1 when STAG2 is absent in Ewing sarcoma cells. Our central hypothesis is that STAG2 loss plays a key role in the epigenetic reprogramming that drives the oncogenic function of EWS/FLI.

项目摘要尤文肉瘤是一种罕见的肿瘤，发生在儿童和年轻人。虽然尤文肉瘤相对罕见，这种疾病的生物学也与非尤因肉瘤和其他癌症亚型有关， EWS/FLI易位的存在，这是这种疾病的驱动事件。类似的易位涉及 ETS转录因子存在于其他恶性肿瘤中，包括前列腺癌。因此，理解尤因肉瘤的生物学可以提供对许多癌症类型的深入了解。我们将研究尤文肉瘤发病机制中的次级遗传事件。这些次要事件已经通过下一代原发性肿瘤和细胞系测序鉴定。具体来说，我们将评估 STAG 2在介导由驱动癌基因诱导的表观遗传和转录变化中的作用，尤文肉瘤，EWS/FLI。在目标1中，我们将使用基因组方法（RNAseq，ChIPseq，WGS等）。来评估 STAG 2在尤文细胞染色质结构、转录和非整倍性调控中的作用在目标2中，我们将使用功能性免疫组化技术，研究STAG 2在尤文肉瘤的进展、维持和转移中的作用。尤文肉瘤细胞系和患者来源的异种移植物的研究。在目标3中，我们将确定是否存在当STAG 2在尤文肉瘤细胞中不存在时，是对STAG 1的合成致死依赖性。我们的中央一种假说认为，STAG 2缺失在表观遗传重编程中起关键作用，表观遗传重编程驱动致癌基因的表达。 EWS/FLI的功能。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules.

DOI：
10.1038/s41467-020-18377-w
发表时间：
2020-09-18
期刊：
Nature communications
影响因子：
16.6
作者：
Nabet B;Ferguson FM;Seong BKA;Kuljanin M;Leggett AL;Mohardt ML;Robichaud A;Conway AS;Buckley DL;Mancias JD;Bradner JE;Stegmaier K;Gray NS
通讯作者：
Gray NS

Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity.

DOI：
10.1126/sciadv.abo3789
发表时间：
2023-03-31
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma.

DOI：
10.1016/j.ccell.2021.07.003
发表时间：
2021-09-13
期刊：
Cancer cell
影响因子：
50.3
作者：
Seong BKA;Dharia NV;Lin S;Donovan KA;Chong S;Robichaud A;Conway A;Hamze A;Ross L;Alexe G;Adane B;Nabet B;Ferguson FM;Stolte B;Wang EJ;Sun J;Darzacq X;Piccioni F;Gray NS;Fischer ES;Stegmaier K
通讯作者：
Stegmaier K

STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.

DOI：
10.1016/j.ccell.2021.05.007
发表时间：
2021-06-14
期刊：
Cancer cell
影响因子：
50.3
作者：
Adane B;Alexe G;Seong BKA;Lu D;Hwang EE;Hnisz D;Lareau CA;Ross L;Lin S;Dela Cruz FS;Richardson M;Weintraub AS;Wang S;Iniguez AB;Dharia NV;Conway AS;Robichaud AL;Tanenbaum B;Krill-Burger JM;Vazquez F;Schenone M;Berman JN;Kung AL;Carr SA;Aryee MJ;Young RA;Crompton BD;Stegmaier K
通讯作者：
Stegmaier K