Interrogation of the Impact of Selection on the Evolution of Human Pancreatic Cancer Precursor Lesions

探究选择对人类胰腺癌前驱病变进化的影响

基本信息

批准号：
10556018
负责人：
Elana Judith Fertig
金额：
$ 54.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556018
关键词：
3-Dimensional Algorithmic Analysis Architecture Automobile Driving Bayesian Modeling Biological Assay Biological Models Cancer Etiology Cells Cessation of life Clonal Evolution Complement Computing Methodologies DNA DNA Sequence Alteration DNA analysis DNA sequencing Data Development Disease Early Diagnosis Event Evolution Excision Experimental Models Foundations Gene Expression Profile Genetic Genetic Heterogeneity Genetic Transcription Genomic Segment Genomics Goals Growth Factor High grade dysplasia Human Hypoxia In Vitro Investigation Knowledge Lesion Malignant neoplasm of pancreas Mediating Mediation Methods Modeling Molecular Molecular Analysis Molecular Computations Mucinous Neoplasm Multiomic Data Mutation Nucleotides Organoids Pancreas Papillary Pathway interactions Pattern Positioning Attribute Premalignant Cell Prevention approach Process Prognosis RNA Research Role Sampling Site Specimen Supervision System Time Tissue Sample Transcriptional Regulation Transforming Growth Factor beta United States Validation Variant Wood material base cancer invasiveness cell growth regulation cohort computer framework data integration deprivation genetic signature genome sequencing human model human tissue in silico innovation insight molecular dynamics multiple omics novel pancreatic neoplasm pancreatic tumorigenesis premalignant pressure prevent single cell analysis single-cell RNA sequencing supervised learning transcriptome sequencing transcriptomics tumor tumor heterogeneity tumor progression whole genome

项目摘要

Project Summary Pancreatic cancer arises from precancerous lesions that are curable if detected and treated early enough. Recent multi-region genomic analyses of one type of precancerous pancreatic lesion, intraductal papillary mucinous neoplasm (IPMN), suggest unique evolutionary and selective pressures in IPMNs compared to invasive cancers, underscoring the potential importance of selection in the progression of precancerous lesions. We propose to characterize the role of selective forces in IPMNs using comprehensive molecular analyses and computational data integration of both human IPMN tissue samples and organoid cultures. We will determine the molecular features of progressed subclones in human IPMN samples using multi-region whole genome sequencing and RNA-sequencing. In addition, we will develop and apply novel multi-omics computational methods to integrate DNA and RNA-sequencing data to delineate selective forces in human IPMNs. We will determine the function of progressed clones identified by whole genome DNA sequencing with gene signatures inferred from bulk transcriptional data in a new semi-supervised framework. We will then employ a three-dimensional in vitro organoid culture model of human IPMN cells to characterize the relative contributions of selective pressures over time. We will use combined DNA sequencing and single-cell RNA- sequencing to identify gene expression signatures of progressed subclones in our organoid model, further adapting our computational framework to single cell RNA-sequencing data. Taken together, the proposed studies combine direct analysis of human tissue samples and manipulation of human precancerous cells in three-dimensional culture with novel multi-omics computational integration to greatly expand our knowledge of the role of selection in pancreatic cancer precursor lesions.

项目摘要胰腺癌是由癌前病变引起的，如果检测到足够早，可以治愈。最近对一种类型的癌性胰腺病变，导管内乳头状的多区域基因组分析粘液肿瘤（IPMN），与IPMN相比，IPMN中的独特进化和选择性压力侵入性癌症，强调选择在癌前的进展中的潜在重要性病变。我们建议使用综合分子来表征选择性力在IPMN中的作用人IPMN组织样品和器官培养物的分析和计算数据整合。我们将使用多区域确定人类IPMN样品中进步子克隆的分子特征整个基因组测序和RNA测序。此外，我们将开发和应用新颖的多摩斯集成DNA和RNA序列数据以描绘人类选择性力的计算方法 IPMN。我们将确定通过与整个基因组DNA测序确定的进步克隆的功能在新的半监督框架中，从批量转录数据推断出的基因特征。然后我们会采用人类IPMN细胞的三维体外器官培养模型来表征相对随着时间的推移，选择性压力的贡献。我们将使用组合的DNA测序和单细胞RNA- 测序以鉴定我们的器官模型中进步亚克隆的基因表达特征，进一步将我们的计算框架调整为单细胞RNA-sequering数据。两者一起，提议研究结合了人类组织样品的直接分析和对人类癌前细胞的操纵具有新颖的多态计算整合的三维文化，以极大地扩展我们对选择在胰腺癌前体病变中的作用。