Impact of cancer predisposition on oncogenic process, microenvironment, and treatment

癌症易感性对致癌过程、微环境和治疗的影响

基本信息

  • 批准号:
    10544995
  • 负责人:
  • 金额:
    $ 46.89万
  • 依托单位:
  • 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:
    2022-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

Our previous study of more than 10 thousand tumors across 33 cancer types identified over 800 germline predisposition variants in both tumor suppressors and oncogenes. Although the impact of some of these variants on cancer onset, incidence rate, and clonality have been documented, the effects of these variants (especially when compared to somatic mutations) on molecular characteristics of cancer cells, contributions of non-cancer cells having germline variants, and treatment responses, are far less studied. Our recent single cell(sc) /single nucleus(sn) RNA-seq analyses of cancer samples provided comprehensive expression profiles at a single cell resolution and revealed the expression of key cancer predisposition genes, such as BRCA 112, VHL, BAP1, and c-MET in many non-cancer stromal and immune cells in the tumor microenvironment (TME). Our pilot analyses also revealed significant differential gene expression in cancer and non-cancer cells based on the nature of the driver event being germline or somatic. We hypothesize that tumors with certain germline predisposition variants in tumor suppressors and oncogenes may show differences in tumor progression and treatment responses from those tumors with somatic mutations in the same genes due to differential influence on mutational, transcriptomic, and proteomic profiles of the cancer cells and potentially distinctive contributions from non-cancer cells having those germline changes. To take advantage of the considerable progress over the last few years, namely newly accumulated cancer sequencing data, advances in single cell omics, patient-derived xenografts (PDX), and tumor genetic models, we propose to test these hypotheses by performing the following: compare germline predisposition variants and somatic mutations to dissect their differential biological impacts and interactions using computational analysis (Aim 1); perform single nucleus RNA-seq/ATAC-seq, spatial transcriptomics, and multiplex imaging analysis of human cancer samples to reveal the differential roles of germline predisposition variants and somatic mutations in tumor cells and the TME (Aim 2); use PDX and genetic cancer models to investigate potential functional differences between germline predisposition variants and somatic mutations in tumor cells, TME, and treatment responses (Aim 3). Results from this study will advance our understanding of the unique contributions of germline variants to cancer cells and TME alike, improve genetic counseling and prognosis, and provide guidance for differential treatment of tumors carrying germline variants vs somatic mutations in key cancer driver genes.
我们之前对 33 种癌症类型的 10,000 多个肿瘤进行的研究发现了 800 多个种系 抑癌基因和癌基因的易感性变异。尽管其中一些影响 变异对癌症发病、发病率和克隆性的影响已被记录,这些变异的影响 (特别是与体细胞突变相比)对癌细胞分子特征的贡献, 具有种系变异的非癌细胞和治疗反应的研究要少得多。我们最近的单曲 癌症样本的细胞(sc)/单核(sn)RNA-seq分析提供了全面的表达谱 以单细胞分辨率揭示了关键癌症易感基因的表达,例如 BRCA 112, 肿瘤微环境 (TME) 中许多非癌基质细胞和免疫细胞中的 VHL、BAP1 和 c-MET。 我们的初步分析还揭示了基于癌症和非癌细胞的基因表达的显着差异 关于驱动事件的性质是种系还是体细胞。我们假设具有某些种系的肿瘤 抑癌基因和癌基因的易感性变异可能在肿瘤进展和预后方面表现出差异 由于差异,相同基因中具有体细胞突变的肿瘤的治疗反应 对癌细胞突变、转录组和蛋白质组谱的影响以及潜在的独特性 来自具有这些种系变化的非癌细胞的贡献。为充分利用可观的 过去几年的进展,即新积累的癌症测序数据、单细胞的进展 组学、患者来源的异种移植物(PDX)和肿瘤遗传模型,我们建议通过以下方式检验这些假设 执行以下操作:比较种系易感性变异和体细胞突变以剖析它们 使用计算分析来区分生物影响和相互作用(目标 1);执行单 人类癌症的核 RNA-seq/ATAC-seq、空间转录组学和多重成像分析 样本揭示种系易感性变异和体细胞突变在肿瘤中的不同作用 细胞和 TME(目标 2);使用 PDX 和遗传癌症模型来研究潜在的功能 肿瘤细胞、TME 和肿瘤细胞中种系易感性变异和体细胞突变之间的差异 治疗反应(目标 3)。这项研究的结果将增进我们对独特的 种系变异对癌细胞和 TME 等的贡献,改善遗传咨询和预后, 并为携带种系变异与关键体细胞突变的肿瘤的差异化治疗提供指导 癌症驱动基因。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

FENG CHEN其他文献

FENG CHEN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('FENG CHEN', 18)}}的其他基金

Impact of cancer predisposition on oncogenic process, microenvironment, and treatment
癌症易感性对致癌过程、微环境和治疗的影响
  • 批准号:
    10367242
  • 财政年份:
    2022
  • 资助金额:
    $ 46.89万
  • 项目类别:
WU-SN-TMC Bio-Analysis Core
WU-SN-TMC 生物分析核心
  • 批准号:
    10376527
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Creating high-resolution multi-omics molecular atlases for developing urogenital organs
创建用于发育泌尿生殖器官的高分辨率多组学分子图谱
  • 批准号:
    10356306
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Washington University Senescence Tissue Mapping Center (WU-SN-TMC)
华盛顿大学衰老组织图谱中心 (WU-SN-TMC)
  • 批准号:
    10376523
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Creating high-resolution multi-omics molecular atlases for developing urogenital organs
创建用于发育泌尿生殖器官的高分辨率多组学分子图谱
  • 批准号:
    10491224
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
WU-SN-TMC Bio-Analysis Core
WU-SN-TMC 生物分析核心
  • 批准号:
    10685428
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Washington University Senescence Tissue Mapping Center (WU-SN-TMC)
华盛顿大学衰老组织图谱中心 (WU-SN-TMC)
  • 批准号:
    10685417
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Creating high-resolution multi-omics molecular atlases for developing urogenital organs
创建用于发育泌尿生殖器官的高分辨率多组学分子图谱
  • 批准号:
    10673765
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Shared Resources Core
共享资源核心
  • 批准号:
    10732989
  • 财政年份:
    2017
  • 资助金额:
    $ 46.89万
  • 项目类别:
Pathogenic Variant Discovery Across a Broad Spectrum of Human Diseases
跨多种人类疾病的致病变异发现
  • 批准号:
    9376872
  • 财政年份:
    2017
  • 资助金额:
    $ 46.89万
  • 项目类别:

相似海外基金

Systems modeling to address the social and biological drivers of disparities in infection and mortality from emerging infectious diseases
用于解决新发传染病感染和死亡率差异的社会和生物驱动因素的系统建模
  • 批准号:
    10669177
  • 财政年份:
    2022
  • 资助金额:
    $ 46.89万
  • 项目类别:
Systems modeling to address the social and biological drivers of disparities in infection and mortality from emerging infectious diseases
用于解决新发传染病感染和死亡率差异的社会和生物驱动因素的系统建模
  • 批准号:
    10415713
  • 财政年份:
    2022
  • 资助金额:
    $ 46.89万
  • 项目类别:
Transporting established insights from classical experimental design to address causal questions in environmental epidemiology including the understanding of biological mediating mechanisms
运用经典实验设计的既定见解来解决环境流行病学中的因果问题,包括对生物介导机制的理解
  • 批准号:
    10395286
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Advancing cryo-EM technology to address difficult biological questions
推进冷冻电镜技术解决棘手的生物学问题
  • 批准号:
    10570241
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Advancing cryo-EM technology to address difficult biological questions
推进冷冻电镜技术解决棘手的生物学问题
  • 批准号:
    10166355
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Advancing cryo-EM technology to address difficult biological questions
推进冷冻电镜技术解决棘手的生物学问题
  • 批准号:
    10376252
  • 财政年份:
    2021
  • 资助金额:
    $ 46.89万
  • 项目类别:
Building Infrastructure to Address Social, Cultural and Biological Determinants of Diabetes in Lebanon
建设基础设施以解决黎巴嫩糖尿病的社会、文化和生物决定因素
  • 批准号:
    10237378
  • 财政年份:
    2020
  • 资助金额:
    $ 46.89万
  • 项目类别:
Reprogramming genetic information at the RNA level: optimizing tools to address specific biological questions
在 RNA 水平上重新编程遗传信息:优化工具来解决特定的生物学问题
  • 批准号:
    404867268
  • 财政年份:
    2018
  • 资助金额:
    $ 46.89万
  • 项目类别:
    Priority Programmes
Biological soil crusts as unique microecosystem represent a suitable model system to address taxonomy and cryptic diversity of microalgal key players
生物土壤结皮作为独特的微生态系统,代表了解决微藻关键参与者的分类学和神秘多样性的合适模型系统
  • 批准号:
    350173788
  • 财政年份:
    2017
  • 资助金额:
    $ 46.89万
  • 项目类别:
    Priority Programmes
Multidisciplinary translational research to address social disparities in osteoporosis: Understanding the social context of biological mechanisms
解决骨质疏松症社会差异的多学科转化研究:了解生物机制的社会背景
  • 批准号:
    nhmrc : 1107510
  • 财政年份:
    2016
  • 资助金额:
    $ 46.89万
  • 项目类别:
    Career Development Fellowships
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了