SWI/SNF chromatin remodelers in tumor-associated antigen-specific CD8+ cytotoxic T cells

肿瘤相关抗原特异性 CD8 细胞毒性 T 细胞中的 SWI/SNF 染色质重塑剂

• 批准号: 10461212
• 负责人: Abhijit Parolia
• 金额: $ 9.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461212
• 关键词: Academia; Address; Affinity; Androgen Receptor; Androgens; Architecture; Automobile Driving; Binding; Bioinformatics; Biological Assay; C-terminal; Cancer Cluster; Castration; Cessation of life; ChIP-seq; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA; DNA Binding Domain; Development; Disease; Disease remission; Doctor of Philosophy; Engineering; Environment; Epigenetic Process; Essential Genes; Foundations; Frameshift Mutation; Future; Genetic; Genetic Enhancer Element; Genetic Transcription; Genomics; Hormone Receptor; Hormones; Incidence; Innovative Therapy; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; Mentors; Metastatic Prostate Cancer; Molecular; Molecular Target; Mutation; Neoplasm Metastasis; Normal Cell; Nuclear; Oncogenes; Oncogenic; Pathogenicity; Pathway interactions; Patients; Peer Review; Phase; Phenotype; Positioning Attribute; Postdoctoral Fellow; Prostate; Proteomics; Publications; Receptor Signaling; Recurrence; Reporter; Research; Research Personnel; Resistance; Role; Sampling; Specific qualifier value; Structure; Therapeutic; Time; Tissues; Training; Tumor Antigens; Variant; WNT Signaling Pathway; Work; base; beta catenin; cancer cell; cancer type; castration resistant prostate cancer; chromatin remodeling; cofactor; cohort; cytotoxic CD8 T cells; epigenomics; experimental study; gain of function; genomic data; improved; innovation; insertion/deletion mutation; insight; malignant breast neoplasm; malignant phenotype; multidisciplinary; mutant; novel; novel therapeutic intervention; overexpression; post-doctoral training; programs; prostate cancer cell; recruit; skills; symposium; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; tumor; tumor progression; tumorigenesis

Project Summary/Abstract: Transcriptional and chromatin dysregulation are hallmarks of cancer. In this project, we functionally characterize alterations in the pioneer transcription factor, called FOXA1, that are highly recurrent in hormone-receptor driven cancers and describe an innovative chromatin-based approach to identify and therapeutically target transcriptional pathways that specify cellular identity in cancer. FOXA1 de-compacts chromatin to enable binding of the androgen receptor (AR) to activate the PCa genes. By leveraging an aggregate PCa cohort with 1546 samples, we define three novel structural classes of FOXA1 alterations that notably diverge in clinical incidence, genomic co-alterations, and pathogenic gain-of-functions. Notably, these three alteration classes collectively recur in over 35% of the cases, making FOXA1 the third most-highly altered oncogene in metastatic PCa. Class1 mutations originate in primary PCa without ETS-fusions or SPOP mutations, alter the Wing2 secondary structure within the DNA-binding domain, enable faster nuclear mobility, and strongly activate the AR program of prostate oncogenesis. Contrastingly, class2 mutations are acquired in the metastatic disease, truncate the C-terminal regulatory domain, enable dominant binding to the chromatin, and activate the WNT program of metastasis. Finally, class3 structural variations are enriched in metastatic PCa, cluster within the FOXA1 topological domain, and duplicate the highly conserved enhancer element that drives overexpression of FOXA1. In the F99 phase, I propose to mechanistically elucidate the neomorphic activation of WNT-signaling by the FOXA1 class2 mutants. I hypothesize the C-terminal domain of WT FOXA1 to recruit WNT-repressive cofactors to the chromatin, and thus the C-terminal truncated class2 mutants that dominantly bind to the chromatin to transcriptionally de-repress WNT-signaling. This hypothesis offers a unique opportunity to uncover a novel association between FOXA1 and WNT transcriptional pathways. In the K00 phase, I aim to address the intriguing question of why driver oncogenes are not universally shared across cancer types. As a likely explanation, I postulate the existence of requisite interactions between oncogenic pathways and lineage-specific epigenetic/chromatin architecture in driving the malignant phenotype, akin to FOXA1 or ERG (oncogenes) and AR (lineage-essential gene) in primary PCa. This presents the opportunity of disrupting these essential, lineage-defining pathways in cancer as a promising therapeutic strategy - a concept termed as “targeting the cancer cell identity.” Overall, our findings till date substantiate FOXA1 as a principal oncogene and a viable therapeutic target in PCa. In the future, I propose to delineate the molecular mechanism of aberrant WNT activation in FOXA1 class2-mutant tumors and propose a novel therapeutic strategy of disrupting the cancer cell identity to improve patient survival. These findings will be presented at research conferences where I can meet with potential K00 mentors, and described in peer-reviewed scientific publications. Training in such a multi-disciplinary environment will provide the foundational knowledge and the essential skills for me to succeed as an independent translational cancer researcher in academia.

项目摘要/摘要： 转录和染色质失调是癌症的标志。在这个项目中，我们在功能上表征 先锋转录因子（称为FOXA1）的改变，在马龙受体驱动器中高度反复出现 癌症并描述一种基于创新的染色质方法，以识别和治疗靶向 转录途径指定癌症中的细胞身份。 FOXA1去压缩染色质以实现结合 雄激素受体（AR）激活PCA基因。通过利用1546的总PCA队列 样本，我们定义了三种新型的FOXA1变化结构类别，这些临床事件在临床事件中显着不同， 基因组共结合和致病性收益。值得注意的是，这三个改动课程集体 在超过35％的病例中，FOXA1在转移性PCA中重复出现。 Class1 突变起源于无ETS合并或SPOP突变的主要PCA，改变Wing2二级结构 在DNA结合域内，启用更快的核迁移率，并强烈激活前列腺的AR程序 肿瘤发生。相反，在转移性疾病中获得了2类突变，将C末端截断 调节结构域，能够与染色质产生显着结合，并激活转移的Wnt程序。 最后，3类结构变化富含转移性PCA，群集在FOXA1拓扑结构域中， 并复制了驱动FOXA1过表达的高度组成的增强元件。在F99阶段，我 提出机械阐明FOXA1 Class2突变体对Wnt信号的新形态激活的建议。 我假设WT FOXA1的C末端结构域将Wnt抑制辅助因子募集到染色质，并且 因此，C末端截短的Class2突变体主要结合染色质与转录抑制作用 wnt信号。该假设为发现Foxa1和Foxa1和 WNT转录途径。在K00阶段，我的目标是解决为什么驱动癌症的有趣问题 不是在癌症类型中普遍共享的。作为一个可能的解释，我假设存在必要的 致癌途径与谱系特异性表观遗传/染色质结构之间的相互作用 原代PCA中的恶性表型，类似于FOXA1或ERG（ONCEGONES）和AR（谱系基因）。这 提出了破坏癌症中这些基本的，定义的谱系途径的机会 治疗策略 - 一种称为“靶向癌细胞身份”的概念。总体而言，我们的发现到目前为止 证明FOXA1是PCA中的主要致癌基因和可行的治疗靶标。将来，我建议 描述FOXA1类突变肿瘤中异常Wnt激活的分子机制和建议 破坏癌细胞身份以改善患者生存的新理论策略。这些发现将是 在我可以与潜在的K00导师会面的研究会议上提出，并在同行评审中进行了描述 科学出版物。在这种多学科环境中的培训将提供基础知识 以及我成为学术界独立翻译的癌症研究员的基本技能。