Engrailed-1 and Epigenetic Vulnerabilities in Metastatic Pancreatic Cancer

转移性胰腺癌中的 Engrailed-1 和表观遗传脆弱性

基本信息

批准号：
10577889
负责人：
Chang-il Hwang
金额：
$ 34.81万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-08 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577889
关键词：
Abbreviations Acceleration Address Alleles Automobile Driving Biomimetics Biopsy Blood Vessels California ChIP-seq Characteristics Coculture Techniques Complex Comprehensive Cancer Center DNA Methylation Data Data Analyses Development Disease Disease Progression Disseminated Malignant Neoplasm Endometrial Carcinoma Endowment Enhancers Epigenetic Process Epithelium Gene Expression Gene Expression Regulation Gene set enrichment analysis Genes Genetic Transcription Genetically Engineered Mouse Glioma Human In Vitro Incidence Injections Invaded Investigation Lung Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of pancreas Mediating Mesenchymal Modeling Molecular Mus Nature Neoplasm Metastasis Organoids Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Patients Play Process Prognosis Property Public Health Renal carcinoma Resected Resistance Role Sampling Solid Neoplasm Stomach Surgical Models System Tail The Cancer Genome Atlas Therapeutic Thyroid Gland Transcription Repressor Tumor-Derived United States Universities Urothelium Veins bisulfite sequencing cancer cell cancer type carcinogenesis chromatin immunoprecipitation chromatin remodeling conditional knockout effective therapy epigenome gain of function genetic signature homeodomain improved in vivo insight loss of function molecular subtypes mortality mouse model neurodevelopment next generation sequencing novel novel therapeutic intervention pancreatic cancer cells pancreatic cancer patients pancreatic ductal adenocarcinoma model patient derived xenograft model recruit single-cell RNA sequencing trait transcription factor transcriptome sequencing transcriptomics transplant model treatment response tumor progression

项目摘要

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.

项目概要/摘要胰腺癌是人类恶性肿瘤中最致命的疾病和有效的治疗方法选择是有限的。在这里，我们假设 Engrailed-1 (EN1)，一种神经发育转录因子，在胰腺癌的进展和转移中发挥着关键作用基因调控的表观遗传机制。 EN1 是同源域转录因子，充当通过招募转录抑制复合物形成转录抑制子。我们的初步数据显示EN1在转移源性类器官和转移病灶中高表达胰腺癌小鼠模型。此外，EN1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 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。我们的数据强烈表明 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，确定 EN1 调节胰腺表观基因组并做出贡献的潜在分子机制 PDA进展和转移。为了解决这个问题，我们将采用多重正交方法了解 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。拟议的研究将为 EN1 介导的表观遗传提供新的见解改变对胰腺癌侵袭性特征的影响。这可能会开辟新的途径胰腺癌的治疗。