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: 10681598
• 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
• 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/10681598
• 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

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 摘要胰腺导管腺癌(PDAC)是一种侵袭性极强的恶性肿瘤，其五年存活期为 不到5%。对人类样本的基因组分析表明，PDAC基本上可以分为 根据癌细胞的自主特性，至少有两种主要亚型：经典亚型和基本样亚型。这两个 亚型具有离散的细胞特性，这反映在几个谱系的差异表达上 指定子，即调节分化状态的转录因子。经典亚型高表达 对前肠内皮细胞决定至关重要的谱系指定物水平(包括HNF4a)。类巴萨尔 亚型表达高水平的转录因子，促进不同的身份，例如 中胚层谱系指定子SIX4和SIX1。此外，碱基样亚型预后较差， 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 这些谱系说明者不仅是PDAC亚型的标记，而且可能调节 这种疾病的恶性潜在性。我们的长期目标是确定PDAC的分子调节因子 子类型，从而确定可能用于治疗的特定于子类型的漏洞。一位少校 这个提议的基本原理是，这个领域必须实现对PDAC分子的机械性理解 亚型规范，以便开发这样的治疗策略。在这项提案中，我们的直接目标是 检验中心假设，包括HNF4α和SIX1/4在内的谱系说明者网络调节PDAC 分子亚型和恶性潜能。我们将在以下特定目标中使用 综合方法，采用基因工程小鼠模型，新的有机培养系统，以及 患者来源的异种移植物：(1)确定不同的hnf4α亚型在pDAC生长中的作用，分子 亚型和药物反应。(2)阐明SIX1和SIX4在PDAC碱基样亚型中的作用。