Project I: Systems analysis of tumor-stroma interactions in brain metastasis

项目一:脑转移中肿瘤-基质相互作用的系统分析

基本信息

  • 批准号:
    10705775
  • 负责人:
  • 金额:
    $ 49.56万
  • 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:
    2022-09-16 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

Project I. Systems Analysis of Tumor-Stroma Interactions in Brain Metastasis Experimental Lead: Massagué Computational Lead: Pe’er PROJECT SUMMARY The overall goal of this project is to apply systems-level computational approaches to mouse models and clinical samples to unravel strategies that metastatic cancer cells employ to colonize the brain. Brain metastasis is a major cause of morbidity and mortality in breast and lung cancer patients. The Massagué Lab pioneered studies to identify mediators of brain metastasis and relevant cell-cell interactions, and are subjecting this problem to systems-level analysis with the Pe’er Lab. We recently found that brain metastatic lesions of triple-negative breast cancer (TNBC), HER2+ breast cancer (HER2BC), and lung adenocarcinoma (LUAD) in mouse models and patient samples display remarkable differences in the spatial relationship between cancer cells and the host tissue. TNBC and LUAD cells spread along brain capillaries via L1CAM, forming perivascular colony networks that intermingle with microglia and astrocytes. In sharp contrast, HER2BC cells colonize the brain by forming compact spheroidal colonies that exclude brain parenchymal cells. High expression of specific extracellular matrix proteins by HER2BC cells drives this spheroidal growth. Notably, the perivascular and spheroidal colonies trigger distinct disease-associated microglia (DAM) innate immunity stages previously defined in Alzheimer’s disease. Aim 1 is to elucidate the DAM regulatory mechanisms in metastasis-associated microglia. We will resolve transcriptional regulation of the homeostasis-to-DAM transition in brain metastasis by analyzing single-cell multiomic profiles of metastasis-associated microglia. We will dissect how cancer cells trigger and modulate DAM responses by testing the hypothesis that HER2BC apoptosis triggers stage 2 DAM, whereas enhanced survival of TNBC retains stage 1 DAM. We will identify drivers of TNBC-intrinsic resistance to apoptosis by computationally guided search for autocrine pro-survival signaling in TNBC cells. We will determine how stage 1 DAM supports tumor growth. We will seek to connect metastasis-associated microglia to activated microglia states across contexts by supervised gene set analysis. Aim 2 is to define spatiotemporal progression and multicellular communication in brain metastasis by a systems-level analysis. We and others have shown the engagement of multiple cell types besides microglia to support brain metastasis. These interactions call for a comprehensive interrogation of the various ensembles of multicellular communication that shape brain metastasis. We will leverage our LUAD-to-brain metastasis models to study “what” cell types and programs constitute multicellular communication ensembles. We will analyze intact metastatic colonies to learn “where” the cells are localized and which programs are differentially expressed. We will unravel “how” the cells and programs shape metastasis by computationally inferring the formation and impact of multicellular ensembles from snapshots of metastatic colonies. We will perturb the inferred ensembles to test therapeutic intervention paradigms. The resulting knowledge, enriched with the input of the CSBC Research Center immunologists and physicians, will ultimately guide the development of therapeutic interventions to target brain metastases. 1
项目一:脑转移中肿瘤-基质相互作用的系统分析

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 }}

JOAN MASSAGUE其他文献

JOAN MASSAGUE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('JOAN MASSAGUE', 18)}}的其他基金

Project I: Systems analysis of tumor-stroma interactions in brain metastasis
项目一:脑转移中肿瘤-基质相互作用的系统分析
  • 批准号:
    10525192
  • 财政年份:
    2022
  • 资助金额:
    $ 49.56万
  • 项目类别:
The TGFÃÂÃÂÃÂò Signaling Pathway in Development and Cancer
发育和癌症中的 TGF 信号通路
  • 批准号:
    10683414
  • 财政年份:
    2020
  • 资助金额:
    $ 49.56万
  • 项目类别:
The TGFÃÂÃÂÃÂò Signaling Pathway in Development and Cancer
发育和癌症中的 TGF 信号通路
  • 批准号:
    10238832
  • 财政年份:
    2020
  • 资助金额:
    $ 49.56万
  • 项目类别:
The TGFÃÂÃÂÃÂò Signaling Pathway in Development and Cancer
发育和癌症中的 TGF 信号通路
  • 批准号:
    10473733
  • 财政年份:
    2020
  • 资助金额:
    $ 49.56万
  • 项目类别:
Residual disease: unraveling immunosurveillance and immune evasion of disseminated tumor cells
残留疾病:解开播散性肿瘤细胞的免疫监视和免疫逃避
  • 批准号:
    9980810
  • 财政年份:
    2016
  • 资助金额:
    $ 49.56万
  • 项目类别:
Brain Metastasis Microenvironment and Mechanisms
脑转移微环境和机制
  • 批准号:
    8555353
  • 财政年份:
    2011
  • 资助金额:
    $ 49.56万
  • 项目类别:
Towards Personalized Cancer Medicine
迈向个性化癌症医学
  • 批准号:
    7805025
  • 财政年份:
    2010
  • 资助金额:
    $ 49.56万
  • 项目类别:
Mechanisms of Metastasis and Evasion of TGF-Beta Tumor Suppression Breast Cancer
TGF-β抑瘤乳腺癌的转移和逃避机制
  • 批准号:
    7438485
  • 财政年份:
    2008
  • 资助金额:
    $ 49.56万
  • 项目类别:
Brain-Specific Metastasis Genes
脑特异性转移基因
  • 批准号:
    7315927
  • 财政年份:
    2007
  • 资助金额:
    $ 49.56万
  • 项目类别:
Project 1: Mediators of Lung Adenocarcinoma Metastatis
项目1:肺腺癌转移的介质
  • 批准号:
    10246296
  • 财政年份:
    2007
  • 资助金额:
    $ 49.56万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了