Engrailed-1 and Epigenetic Vulnerabilities in Metastatic Pancreatic Cancer

项目摘要/摘要 胰腺癌是人类最致命的恶性肿瘤和有效的治疗方法。 选择是有限的。在这里，我们假设渐进式1(EN1)，一种神经发育 转录因子在胰腺癌的进展和转移中起关键作用 基因调控的表观遗传机制。EN1是一种同源结构域转录因子，其作用是 通过招募转录抑制复合体的转录抑制因子。我们的预赛 数据显示，EN1在转移衍生器官和转移灶中高度表达 建立小鼠胰腺癌模型。此外，EN1的表达与预后不良有关 胰腺癌的鳞状分子亚型。在这里，我们发现EN1表达式 赋予胰腺癌细胞侵袭性并诱导鳞状PDA 身份基因签名。我们的数据有力地表明，EN1介导的表观遗传改变 为转移性胰腺癌创造了新的脆弱性。因此，关键是要确定 EN1调控胰腺表观基因组及其贡献的潜在分子机制 与动脉导管未闭的进展和转移有关。为了解决这个问题，我们将使用多正交方法 了解EN1在PDA进展中的确切作用。在这里，我们建议1)确定 EN1在胰腺癌表观基因组中的作用，以及2)确定EN1在胰腺癌中的作用 癌症进展。这项拟议的研究将提供一个新的洞察力，即EN1介导的表观遗传学 基因改变对胰腺癌侵袭性特征的影响。这可能会为 胰腺癌的治疗。

Project Summary/Abstract Pancreatic cancer is the most deadly disease in human malignancies and effective treatment options are limited. Here, we hypothesize that Engrailed-1 (EN1), a neuro-development transcription factor, plays a critical role in pancreatic cancer progression and metastasis via epigenetic mechanism of gene regulation. EN1 is a homeo-domain transcription factor, acting as a transcriptional repressor via recruiting transcriptional repressive complexes. Our preliminary data show that EN1 is highly expressed in metastasis-derived organoids and metastatic lesions of pancreatic cancer mouse model. In addition, EN1 expression is associated with poor prognosis and the squamous molecular subtype of pancreatic cancer. Here, we find that EN1 expression endows aggressive characteristics to pancreatic cancer cells and induces the squamous-PDA identity gene signature. Our data strongly suggest that EN1-mediated epigenetic alterations create a new vulnerability for metastatic pancreatic cancer. Therefore, it is critical to identify the underlying molecular mechanism by which EN1 regulates pancreatic epigenome and contributes to PDA progression and metastasis. To address this, we will employ multi-orthogonal approaches to understand the precise role of EN1 in PDA progression. Here, we propose 1) to determine the role of EN1 in the pancreatic cancer epigenome, and 2) to determine the role of EN1 in pancreatic cancer progression. The proposed study will provide a new insight how EN1-mediated epigenetic alterations impact on aggressive traits of pancreatic cancer. This may open novel avenues for the treatment of pancreatic cancer.