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
- 来源:
- 关键词:Adenocarcinoma CellAlzheimer&aposs DiseaseApoptosisAstrocytesBasement membraneBindingBlood VesselsBrainBreast Cancer CellCancer PatientCell CommunicationCellsClinicalCommunicationComplexDisease associated microgliaDisseminated Malignant NeoplasmERBB2 geneExclusionExtracellular Matrix ProteinsFactor AnalysisGene ExpressionGenesGeneticGenetic TranscriptionGoalsGrowthHomeostasisImmuneImmune systemImmunologistLabelLamininLeadLearningLogicLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMediatingMediatorMemorial Sloan-Kettering Cancer CenterMetastatic malignant neoplasm to brainMicrogliaModelingMorbidity - disease rateNatural ImmunityNatureNeoplasm MetastasisNeural Cell Adhesion Molecule L1PatientsPhenotypePhysiciansPrimary NeoplasmResearchResearch PersonnelResistanceSamplingShapesSignal TransductionSystemSystems AnalysisSystems BiologyTestingTherapeutic InterventionTissuesTranscriptional Regulationautocrinebrain cellbrain shapecancer cellcell typecerebral capillarycontextual factorsdifferential expressionknowledge of resultslung colonizationmalignant breast neoplasmmortalitymouse modelmultiple omicspharmacologicpreventprogramsresponsesingle cell analysissingle-cell RNA sequencingspatial relationshipspatiotemporaltherapeutic developmenttherapeutic evaluationtriple-negative invasive breast carcinomatumortumor growthunpublished works
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.
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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)
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JOAN MASSAGUE其他文献
JOAN MASSAGUE的其他文献
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{{ 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:
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:
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:














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