Project 1: Elucidating the genetics and cell of origin of pancreatic cancer initiation

项目1：阐明胰腺癌发生的遗传学和细胞起源

基本信息

批准号：
10187125
负责人：
LAURA D ATTARDI
金额：
$ 43.8万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10187125
关键词：
Acinar Cell Affect Aging Alleles Bar Codes CDKN2A gene CRISPR/Cas technology Cells Clinical Clinical Management Clonal Expansion Data Development Disease Duct (organ) structure Ductal Epithelial Cell Early Diagnosis Early treatment Epithelial Cells Event Evolution Gene Expression Gene Expression Profile Genetic Genetic Determinism Genetically Engineered Mouse Genotype High-Throughput Nucleotide Sequencing Homeostasis Human Immune Intervention KRAS oncogenesis KRAS2 gene KRASG12D Knowledge Lead Lesion MADH4 gene Malignant Neoplasms Malignant neoplasm of pancreas Maps Measures Metaplasia Modeling Molecular Mus Mutate Mutation Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatitis Pathway interactions Positioning Attribute Process Recurrence Research Research Personnel Risk Risk Factors Role Route Symptoms System TP53 gene Testing Tumor Suppressor Genes Tumor-Derived Tumor-Suppressor Gene Inactivation Variant Viral cancer care cancer cell cancer genetics cancer initiation carcinogenesis cell type chronic pancreatitis design genome editing genome sequencing immunoregulation improved in vivo innovation insight mortality mouse model mutant neoplastic novel premalignant regenerative repaired single-cell RNA sequencing somatic cell gene editing synergism transcriptome transdifferentiation tumor tumor initiation tumor microenvironment

项目摘要

ABSTRACT (Project 1) Pancreatic ductal adenocarcinoma (PDAC) is a prevalent and almost uniformly fatal malignancy. Human PDAC genome sequencing has identified recurrent mutations in Kras and several major tumor suppressor genes (TSGs), but the impact of these alterations in the initiation and evolution of human PDAC development remain poorly understood at the molecular level. Understanding the basis of tumor initiation and development has critical implications for improving early diagnosis and therapy. While PDACs were originally thought to arise from ductal cells, evidence from mouse models suggests that acinar cells can give rise to PDACs through a regenerative, transdifferentiation process known as Acinar to Ductal Metaplasia (ADM). ADM is stimulated by chronic pancreatitis, a known risk factor for PDAC, and generates premalignant Pancreatic Intraepithelial Neoplasias (PanINs), which lead to PDAC. Our preliminary data suggest that the p53 TSG can inhibit ADM and that p53 inactivation in acinar cells expressing oncogenic KrasG12D drives PDAC. However, expression of oncogenic KrasG12D and p53 inactivation in ductal cells can also induce PDAC, suggesting alternate routes of PDAC carcinogenesis. Interestingly, we find that acinar cell-derived and ductal cell-derived tumors resemble the classical and basal-like subtypes of human PDAC, respectively. These results underscore the unique value of mouse models in uncovering the determinants that dictate different paths of PDAC evolution to provide insight into human PDAC. The roles of other common PDAC TSGs in early stage pre-neoplastic lesions, including whether they normally function in acinar cells and/or ductal cells, however, remains unclear. Furthermore, oncogenic Kras mutations are diverse in PDAC, yet it is unknown whether different mutations have distinct impacts on PDAC development from different pancreatic epithelial cell types. We hypothesize that the cell type of origin and tumor genotype cooperate to drive different paths of PDAC development, and to test this idea, we will systematically inactivate several major PDAC TSGs and express different Kras alleles in both putative cell types of origin. We will characterize the transcriptomes and the cellular milieu of early lesions and tumors and employ innovative approaches like somatic genome editing and molecular barcoding. We will compare our studies in tractable mouse models to studies of human PDAC development. Together, these transformative studies will establish how genetic determinants and cell-of-origin influence the molecular pathways and the cellular microenvironment during PDAC evolution in mice and humans, critical knowledge for better clinical management of this deadly disease.

摘要（项目1）胰腺导管腺癌（PDAC）是一种普遍且几乎都是致命的恶性肿瘤。人类PDAC 基因组测序发现了 Kras 和几个主要肿瘤抑制基因的反复突变（TSG），但这些改变对人类 PDAC 发育的起始和进化的影响仍然存在在分子水平上了解甚少。了解肿瘤发生和发展的基础至关重要对改善早期诊断和治疗的影响。虽然 PDAC 最初被认为是由导管产生的来自小鼠模型的证据表明，腺泡细胞可以通过再生、转分化过程称为腺泡到导管化生 (ADM)。 ADM 受到慢性刺激胰腺炎是 PDAC 的已知危险因素，可产生癌前胰腺上皮内瘤变 (PanIN)，从而导致 PDAC。我们的初步数据表明 p53 TSG 可以抑制 ADM，并且 p53 表达致癌性 KrasG12D 的腺泡细胞失活可驱动 PDAC。然而，致癌物质的表达导管细胞中 KrasG12D 和 p53 失活也可诱导 PDAC，提示 PDAC 的替代途径致癌作用。有趣的是，我们发现腺泡细胞来源的肿瘤和导管细胞来源的肿瘤类似于分别为人类 PDAC 的经典亚型和基底样亚型。这些结果强调了其独特的价值小鼠模型揭示了决定 PDAC 进化不同路径的决定因素，以提供见解进入人类 PDAC。其他常见 PDAC TSG 在早期肿瘤前病变中的作用，包括然而，它们是否在腺泡细胞和/或导管细胞中正常发挥作用仍不清楚。此外， PDAC 中致癌的 Kras 突变多种多样，但尚不清楚不同的突变是否具有不同的作用。不同胰腺上皮细胞类型对 PDAC 发育的影响。我们假设细胞类型起源和肿瘤基因型合作驱动 PDAC 发展的不同路径，为了检验这个想法，我们将系统地灭活几个主要的 PDAC TSG，并在两个假定细胞中表达不同的 Kras 等位基因产地类型。我们将表征早期病变和肿瘤的转录组和细胞环境，采用体细胞基因组编辑和分子条形码等创新方法。我们将比较我们的从易驯服小鼠模型研究到人类 PDAC 发育研究。在一起，这些变革性的研究将确定遗传决定因素和细胞起源如何影响分子途径和小鼠和人类 PDAC 进化过程中的细胞微环境，更好临床的关键知识控制这种致命疾病。