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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：
10400085
负责人：
Eric Lee Snyder
金额：
$ 34.27万
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/10400085
关键词：
ATAC-seq Biology Cell Line ChIP-seq 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 Property Protein Isoforms Research Role Sampling Short Interspersed Nucleotide Elements Specific qualifier value System Testing Therapeutic Tissues Work base cancer cell cell regeneration chemotherapy clinically relevant 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 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.

项目摘要胰腺导管腺癌（PDAC）是一种侵袭性极强的恶性肿瘤，不到5%。人类样本的基因组分析表明，PDAC基本上可以分为基于癌细胞自主性质的至少两种主要亚型：经典型和基底样型。这两亚型具有离散的细胞特性，如几个谱系的差异表达所反映的。说明符，即调节分化状态的转录因子。经典亚型表达高前肠内胚层决定关键的谱系特异性因子水平（包括HNF 4A）。基底样亚型表达高水平的转录因子，促进替代身份，如中胚层谱系说明符SIX 4和SIX 1。此外，基底样亚型预后差，与经典亚型相比，对一线化疗的反应较差。这些相关性提高了这些谱系特异性不仅仅是PDAC亚型的标志物，而且可能调节PDAC亚型的表达。这种疾病的恶性潜力。我们的长期目标是确定PDAC的分子调节因子子类型，从而识别可能被治疗性利用的子类型特异性弱点。一个主要这个建议的基本原理是，该领域必须实现对PDAC分子的机理理解亚型规范，以便开发这样的治疗策略。在这项建议中，我们的近期目标是检验核心假设，即包括HNF 4 α和SIX 1/4在内的谱系特异性网络调节PDAC 分子亚型和恶性潜能。我们将使用以下特定目标来测试这一假设采用基因工程小鼠模型、新型类器官培养系统和患者来源的异种移植物：（1）确定不同HNF 4 α亚型在PDAC生长中的作用，分子生物学亚型和药物反应。(2)阐明SIX 1和SIX 4在基底细胞样PDAC亚型中的作用。