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

项目摘要/摘要： 转录和染色质失调是癌症的特征。在这个项目中，我们从功能上描述 在激素受体驱动的情况下，称为FOXA1的先锋转录因子的变化是高度重复的 并描述了一种基于染色质的创新方法来识别和治疗靶点 在癌症中指定细胞身份的转录途径。FOXA1解压染色质以实现结合 雄激素受体(AR)来激活PCA基因。通过利用1546人的聚合PCA队列 样本，我们定义了FOXA1改变的三个新的结构类别，它们在临床发病率上明显不同， 基因组共变和致病功能获得。值得注意的是，这三个变更类加在一起 超过35%的病例复发，使FOXA1成为转移性前列腺癌中第三大高度改变的癌基因。类别1 突变起源于原发PCa，没有ETS融合或SPOP突变，改变Wing2二级结构 在DNA结合域内，实现更快的核移动，并强烈激活前列腺的AR程序 致癌作用。相比之下，在转移性疾病中获得了2个突变，截断了C-末端 调节结构域，使显性结合到染色质，并激活转移的WNT程序。 最后，在FOXA1拓扑域内的转移性PCA、簇中富含class3结构变异， 并复制驱动FOXA1过表达的高度保守的增强子元件。在F99阶段，我 建议从机制上阐明FOXA1 2突变体对WNT信号的新形态化激活。 我假设WT FOXA1的C-末端结构域将WNT抑制辅助因子招募到染色质中，并且 因此，C末端被截短的主要与染色质结合的2个突变体在转录上降低了抑制 WNT-发信号。这一假说提供了一个独特的机会来揭示FOXA1和FOXA1之间的新关联 WNT转录途径。在K00阶段，我的目标是解决一个耐人寻味的问题：为什么驱动癌基因 并不是所有癌症类型都有相同的基因。作为一种可能的解释，我假设必需品的存在 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 恶性表型，类似于原发性前列腺癌的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基本的、谱系定义的途径的机会，作为一种有希望的 治疗策略--一个被称为“靶向癌细胞身份”的概念。总体而言，我们到目前为止的调查结果 证实FOXA1是前列腺癌的主要癌基因和可行的治疗靶点。在未来，我建议 阐明FOXA1基因突变肿瘤中WNT异常激活的分子机制，并提出 破坏癌细胞特性以提高患者存活率的新治疗策略。这些发现将是 在研究会议上发表，在那里我可以会见潜在的K00导师，并在同行评议中描述 科学出版物。在这样一个多学科的环境中进行培训将提供基础知识 以及我在学术界作为一名独立的癌症翻译研究人员取得成功所需的基本技能。

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.