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

项目概要/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FOXA 1的先驱转录因子的改变，在受体驱动的细胞中高度复发， 并描述了一种创新的基于染色质的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。FOXA 1使染色质解聚以实现结合 雄激素受体（AR）激活PCa基因。通过利用具有1546名患者的聚合PCa队列， 样本中，我们定义了三种新的FOXA 1改变的结构类别，它们在临床发病率上明显不同， 基因组共改变和致病性功能获得。值得注意的是，这三个变更类别共同 在超过35%的病例中复发，使FOXA 1成为转移性PCa中第三大高度改变的癌基因。Class1 突变起源于原发性PCa，没有ETS融合或SPOP突变，改变Wing 2二级结构 在DNA结合结构域内，使细胞核移动更快，并强烈激活前列腺的AR程序 肿瘤发生相比之下，在转移性疾病中获得class 2突变，截短C末端， 调节结构域，使显性结合染色质，并激活转移的WNT程序。 最后，class 3结构变异在转移性前列腺癌中富集，聚集在FOXA 1拓扑结构域内， 并复制驱动FOXA 1过表达的高度保守的增强子元件。在F99阶段，我 提出的机制阐明新形态激活WNT信号的FOXA 1 class 2突变体。 我假设WT FOXA 1的C-末端结构域将WNT抑制性辅因子募集到染色质中， 因此，C-末端截短的class 2突变体主要与染色质结合， WNT信令。这一假说提供了一个独特的机会，揭示了FOXA 1与 WNT转录途径。在K 00阶段，我的目标是解决一个有趣的问题，为什么驱动癌基因 并不是所有的癌症类型都一样。作为一个可能的解释，我假设存在必要的 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 恶性表型，类似于原发性PCa中的FOXA 1或ERG（癌基因）和AR（谱系必需基因）。这 提出了一个有希望的机会，破坏这些必要的，谱系定义的途径在癌症中， 治疗策略-称为“靶向癌细胞身份”的概念。总的来说，我们迄今为止的发现 证实FOXA 1是PCa的主要癌基因和可行的治疗靶点。今后，我建议 描述FOXA 1 2类突变肿瘤中异常WNT激活的分子机制，并提出一种新的治疗方法。 破坏癌细胞身份以提高患者存活率的新治疗策略。这些发现将是 在研究会议上提出，我可以会见潜在的K 00导师，并在同行评审中描述 科学出版物。在这样一个多学科环境中的培训将提供基础知识 以及我作为一名独立的转化型癌症研究者在学术界取得成功的基本技能。

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.