权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defining the role of chromatin remodeling complexes in pancreatic cancer stem cells

定义染色质重塑复合物在胰腺癌干细胞中的作用

基本信息

批准号：
10090454
负责人：
Lesley Paige Ferguson
金额：
$ 3.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-06 至 2022-01-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090454
关键词：
Anchorage-Independent Growth Automobile Driving Cancer Etiology Cancer cell line Cells Cessation of life ChIP-seq Characteristics Chromatin Chromatin Remodeling Factor Complement Complex Data Dependence Developed Countries Development Diagnosis Disease Disease Progression Epigenetic Process Genetic Models Genetic Transcription Genetically Engineered Mouse Goals Growth Heterogeneity Human In Vitro KRAS2 gene Knock-in Knock-out Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediator of activation protein Medical Modeling Neoplasm Metastasis Nucleosomes Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patients Pattern Population Publishing Refractory Relapse Reporter Resistance Role SMARCD3 gene SWI/SNF Family Complex Signal Transduction Survival Rate System TP53 gene Testing Widespread Disease Work Xenograft procedure base cancer initiation cancer stem cell chemotherapy chromatin remodeling differential expression epigenetic regulation histone modification human disease human model improved in vivo mouse genetics mouse model novel novel therapeutics pancreatic cancer cells pancreatic cancer model pancreatic cancer patients patient derived xenograft model programs response small hairpin RNA stem stem cell expansion stem cell growth stem cell population stem cells stemness therapy resistant transcriptome transcriptome sequencing treatment response tumor tumor growth tumor progression

项目摘要

Project Summary Pancreatic adenocarcinoma (PDAC) is a devastating disease characterized by high rates of metastasis and poor therapeutic response. It is currently the 4th leading cause of cancer related deaths in developed countries and despite efforts to improve therapy, the five-year survival rate remains at 9%. Therefore it is critical to identify new programs that drive pancreatic cancer progression and therapeutic resistance. To define new cancer dependencies, work in the Reya lab has focused on characterizing stem cell programs that drive cancer initiation, propagation, and relapse. Previously published studies have demonstrated that the fate determinant Musashi2 functionally marks a stem population in pancreatic cancer, and more recent work has revealed that this stem cell population is characterized by a highly unique transcriptional and epigenetic profile. Given the crucial role for epigenetic regulation in development and dysregulation in cancer, it is logical to hypothesize that differentially expressed epigenetic regulatory factors could be responsible for the establishment or maintenance of this unique stem cell state in pancreatic cancer. Using functional screens to profile the impact of inhibition of candidate epigenetic factors on stem cells in vitro, the gene Smarcd3 has been identified as a potential critical mediator of stem cell growth in pancreatic cancer. Smarcd3 encodes Baf60c, a component of the SWI/SNF nucleosome remodeling complex that is known to be dysregulated in pancreatic cancer. Preliminary studies have shown that Smarcd3 inhibition leads to reduced growth of KPf/fC pancreatic cancer stem cells in vitro and in vivo. Smarcd3 inhibition also leads to reduced anchorage-independent growth of human pancreatic cancer cell lines in vitro. Based on these data, the aims of this proposal are to test the hypotheses that (1) Smarcd3 is required for pancreatic cancer growth and stem cell expansion in genetically engineered mouse models, and (2) Smarcd3 is required for growth of human pancreatic cancer cell lines and patient-derived pancreatic cancer xenografts.

项目总结