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

• 批准号: 10504285
• 负责人: Eric Lee Snyder
• 金额: $ 1.74万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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/10504285
• 关键词: Disease; Genetically Engineered Mouse; Genomics; Goals; Growth; HNF4A gene; Human; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular; Organoids; Pancreatic Ductal Adenocarcinoma; Pharmaceutical Preparations; Primitive foregut structure; Prognosis; Property; Protein Isoforms; Research; Role; Sampling; System; Testing; Therapeutic; base; cancer cell; chemotherapy; design; differential expression; molecular subtypes; novel; patient derived xenograft model; response; transcription factor

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 HNF4 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 HNF4 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， 小于5%。人类样本的基因组分析表明，PDAC从根本上可以分为 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的分子调节剂 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 检验一个核心假设，即包括HNF 4 β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 β亚型在PDAC生长中的作用， 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。