Engrailed-1 and Epigenetic Vulnerabilities in Metastatic Pancreatic Cancer

项目总结/摘要 胰腺癌是人类恶性肿瘤中死亡率最高的疾病，治疗效果最好 选择有限。在这里，我们假设Engrailed-1（EN 1），一种神经发育 在胰腺癌的进展和转移中起着关键作用， 基因调控的表观遗传机制。EN 1是一种同源结构域转录因子， 通过募集转录抑制复合物来抑制转录。我们的初步 数据显示EN 1在转移源性类器官和转移性病变中高度表达 胰腺癌小鼠模型。此外，EN 1表达与不良预后相关 和胰腺癌的鳞状分子亚型。在这里，我们发现EN 1表达 赋予胰腺癌细胞侵袭性，诱导鳞状PDA 身份基因签名。我们的数据强烈提示EN 1介导的表观遗传改变 为转移性胰腺癌创造了新的弱点因此，确定 EN 1调节胰腺表观基因组并促进胰腺癌发生的潜在分子机制 动脉导管未闭的进展和转移为了解决这个问题，我们将采用多正交方法 了解EN 1在PDA进展中的确切作用。在这里，我们建议1）确定 EN 1在胰腺癌表观基因组中的作用，和2）确定EN 1在胰腺癌表观基因组中的作用， 癌症进展这项研究将为EN 1介导的表观遗传学提供新的见解。 改变影响胰腺癌的侵袭性特征。这可能会打开新的途径， 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.