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: 10452046
• 负责人: Abhijit Parolia
• 金额: $ 8.91万
• 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/10452046
• 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，我们从功能上描述了 称为 FOXA1 的先锋转录因子的改变，在激素受体驱动的过程中高度反复出现 癌症并描述了一种基于染色质的创新方法来识别和治疗目标 指定癌症中细胞身份的转录途径。 FOXA1 使染色质解压缩以实现结合 雄激素受体 (AR) 激活 PCa 基因。通过利用总计 1546 名 PCa 队列 样本中，我们定义了 FOXA1 改变的三种新的结构类别，它们在临床发生率上显着不同， 基因组共同改变和致病性功能获得。值得注意的是，这三个改变类共同 超过 35% 的病例会复发，这使得 FOXA1 成为转移性 PCa 中第三个最高度改变的癌基因。 1级 突变起源于没有 ETS 融合或 SPOP 突变的原发性 PCa，改变 Wing2 二级结构 DNA结合域内，实现更快的核迁移，并强烈激活前列腺的AR程序 肿瘤发生。相比之下，2 类突变是在转移性疾病中获得的，截断 C 末端 调节域，能够与染色质显性结合，并激活 WNT 转移程序。 最后，3 类结构变异在转移性 PCa 中丰富，在 FOXA1 拓扑域内聚集， 并复制驱动 FOXA1 过度表达的高度保守的增强子元件。在F99阶段，我 提议从机制上阐明 FOXA1 2 类突变体对 WNT 信号传导的新形态激活。 我假设 WT FOXA1 的 C 端结构域将 WNT 抑制辅助因子招募到染色质，并且 因此，C 端截短的 2 类突变体主要与染色质结合，以解除转录抑制 WNT-信号传导。这一假设提供了一个独特的机会来揭示 FOXA1 和 WNT 转录途径。在 K00 阶段，我的目标是解决一个有趣的问题：为什么驱动癌基因 不同癌症类型之间并不普遍共有。作为一种可能的解释，我假设存在必要的条件 致癌途径和谱系特异性表观遗传/染色质结构之间的相互作用在驱动 恶性表型，类似于原发性 PCa 中的 FOXA1 或 ERG（癌基因）和 AR（谱系必需基因）。这 提供了破坏癌症中这些重要的谱系定义途径的机会，作为一种有前途的方法 治疗策略 - 一个称为“针对癌细胞身份”的概念。总的来说，迄今为止我们的发现 证实 FOXA1 是 PCa 的主要癌基因和可行的治疗靶点。未来我提议 描述了 FOXA1 2 类突变肿瘤中异常 WNT 激活的分子机制，并提出了一种 破坏癌细胞身份以提高患者生存率的新治疗策略。这些发现将 在研究会议上发表，我可以在那里与潜在的 K00 导师会面，并在同行评审中进行了描述 科学出版物。在这样的多学科环境中进行培训将提供基础知识 以及我作为学术界独立转化癌症研究员取得成功的基本技能。