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

Lineage specifiers governing pancreatic cancer growth and molecular subtype

控制胰腺癌生长和分子亚型的谱系说明符

基本信息

批准号：
10738018
负责人：
Eric Lee Snyder
金额：
$ 6.47万
依托单位：
UNIVERSITY OF UTAH
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：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738018
关键词：
ATAC-seq Biology Cell Line ChIP-seq Classification Data Development Differentiation and Growth Disease Exhibits Family Gene Expression Genes Genetically Engineered Mouse Genomics Goals Growth HNF4A gene Homeobox Human In Vitro Knowledge Lysine Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Measures Mesenchymal Molecular Mus Muscle satellite cell Normal tissue morphology Oncogenes Organoids Pancreatic Ductal Adenocarcinoma Pattern Pharmaceutical Preparations Play Primitive foregut structure Prognosis Proliferating Property Protein Isoforms Repression Research Role Sampling Specific qualifier value System Testing Therapeutic Tissues Work cancer cell cell regeneration chemotherapy clinically relevant cofactor design differential expression experimental study gene regulatory network in vitro Model in vivo insight loss of function member molecular subtypes mouse model novel pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model patient derived xenograft model progenitor programs promoter response restraint stem cell function stem cell proliferation transcription factor transcriptome transcriptomics tumor tumor growth

项目摘要

Project summary Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with a five-year survival of less than 5%. Genomic analyses of human samples suggest that PDAC can fundamentally be classified into at least two major subtypes based on cancer cell autonomous properties: Classical and Basal-like. These two subtypes have discrete cellular identities, as reflected by the differential expression of several lineage specifiers, i.e. transcription factors that regulate differentiation state. The Classical subtype expresses high levels of lineage specifiers pivotal for foregut endodermal determination (including HNF4A). The Basal-like subtype expresses high levels of transcription factors promoting alternative identities, such as the mesodermal lineage specifiers SIX4 and SIX1. Moreover, the Basal-like subtype confers poor prognosis and responds less well to first-line chemotherapy compared to the Classical subtype. These correlations raise the possibility that these lineage specifiers are not merely markers of PDAC subtype, but might regulate the malignant potential of this disease. Our long-term goal is to identify the molecular regulators of PDAC subtype and thereby identify subtype-specific vulnerabilities that might be exploited therapeutically. A major rationale for this proposal is that the field must achieve a mechanistic understanding of PDAC molecular subtype specification in order to develop such therapeutic strategies. In this proposal, our immediate goal is to test the central hypothesis that a network of lineage specifiers, including HNF4α and SIX1/4, regulates PDAC molecular subtype and malignant potential. We will test this hypothesis in the following specific aims using an integrative approach that employs genetically engineered mouse models, novel organoid culture systems, and patient derived xenografts: (1) Determine the role of distinct HNF4α isoforms in PDAC growth, molecular subtype and drug response. (2) Elucidate the function of SIX1 and SIX4 in the Basal-like subtype of PDAC.

项目总结