Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer
Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer
批准号:
10819066
负责人:
Christina N Curtis
金额:
$6.62万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-14 至 2025-08-31
关键词:
3-DimensionalAddressBiological ModelsBreastBreast Cancer ModelBreast Cancer PatientBreast cancer metastasisCRISPR screenCRISPR/Cas technologyCancer RelapseCell CommunicationCellsClassificationClinicalCollectionComputer ModelsDataDependenceDevelopmentDiagnosisDiseaseERBB2 geneEstrogen receptor positiveExperimental ModelsGenomic approachGenomicsGoalsImageImmuneImmune systemIn SituLeadLongitudinal cohortMachine LearningMacrophageMalignant NeoplasmsMetastatic breast cancerModelingMolecularMolecular ProfilingMultiplexed Ion Beam ImagingNatureNeoplasm MetastasisNon-linear ModelsOncogenicOrganoidsOutcomePathologistPathologyPatientsPhagocytosisPopulationPrimary NeoplasmProcessPropertyRelapseResearch Project GrantsResearch SupportResistanceResolutionResource SharingSamplingSiteSpatial DistributionSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationStromal CellsSubgroupSystemSystems BiologyTechnologyTherapeuticTimeTissue ModelTissue SampleTissuesTumor TissueVisionVisualizationbeanbiobankbreast cancer progressioncancer cellcohortcomputer frameworkcomputerized toolsdata integrationdisease heterogeneityfunctional genomicsgenome-widehigh riskhormone therapyinnovationinventionmalignant breast neoplasmmultidisciplinaryneoplastic cellprospectiverelapse riskresponsesingle cell technologytargeted treatmenttherapeutic targettherapy resistanttissue resourcetriple-negative invasive breast carcinomatumor
中文摘要
摘要/项目摘要
转移性乳腺癌和治疗后复发取决于(1)内在耐药性的发展
靶向治疗和内分泌治疗,以及(2)对癌细胞的识别和破坏的抗性,
免疫系统斯坦福大学乳腺癌转移中心(SBMC)专注于(1)量化
乳腺癌的转移性播散(2)功能性描述细胞和
微环境对转移倾向的干扰,以及(3)通过以下方式表征响应机制:
转移细胞的治疗方法。
为了实现这些目标,机械计算模型,捕捉动态和
需要新出现的肿瘤细胞的内在和外在特性,
组织队列和实验模型,捕捉疾病的异质性。SBMC解决了所有这些问题
突出的挑战。首先,我们已经建立了一个无与伦比的收集临床注释乳腺癌
通过治疗和转移采样的癌症队列,包括前瞻性和回顾性
纵向队列,具有多个转移部位。我们利用乳腺癌患者的活体生物库-
来自原发性肿瘤和转移瘤的衍生类器官(PDO),
疾病,高风险复发亚组和肿瘤免疫相互作用,并大大促进了拟议的
功能研究。我们使用最先进的技术来表征这些巨大的组织资源和模型系统,
分子分析技术,以单细胞和亚细胞分辨率原位探测肿瘤组织。具体地说,
通过飞行时间多路离子束成像(MIBI-TOF)和基质辅助激光解吸电离
MALDI成像(MALDI)可以同时显示肿瘤的组成,谱系,功能和空间分布
和基质细胞群,并进行糖组的共配准分析。我们将这些数据整合到
转移性疾病的基因组景观,并在强大的机器学习中分析这些数据,
计算框架来揭示与临床结果相关的疾病动力学和特征。
最后,我们在3D乳腺癌模型中进行基因组规模的CRISPR筛选,以系统地定义
致癌依赖性、治疗脆弱性和巨噬细胞-肿瘤细胞相互作用。
这种整合的系统生物学和功能基因组学方法将有助于定量和
转移性乳腺癌的机制理解以及肿瘤细胞与
宿主,并对治疗靶向产生影响。
英文摘要
Abstract/Project Summary
Metastatic breast cancer and relapse following therapy are dependent on (1) development of intrinsic resistance
to targeted and endocrine therapies, and (2) resistance to recognition and destruction of cancer cells by the
immune system. The Stanford Breast Metastasis Center (SBMC) is focused on (1) quantifying the timing of
metastatic dissemination in breast cancer (2) functionally delineating the contribution of cellular and
microenvironmental crosstalk on metastatic proclivity, and (3) characterizing the mechanisms of responses by
metastatic cells to therapies.
In order to achieve these goals, mechanistic computational models that capture dynamic and
emergent tumor cell intrinsic and extrinsic properties are needed as are clinically annotated longitudinal
tissue cohorts and experimental models that capture disease heterogeneity. The SBMC addresses each of these
outstanding challenges. First, we have established an unparalleled collection of clinically annotated breast
cancer cohorts sampled through treatment and metastasis, including both prospective and retrospective
longitudinal cohorts, with multiple metastatic sites. We leverage a living biobank of breast cancer patient-
derived organoids (PDOs) from primary tumors and metastases that recapitulate the heterogeneity of
disease, high-risk of relapse subgroups and tumor-immune interactions and greatly facilitating the proposed
functional studies. We characterize these vast tissue resources and model systems using state-of-the-art
molecular profiling technologies to probe tumor tissue in situ at single cell and subcellular resolution. Specifically,
with Multiplexed Ion Beam Imaging by Time of Flight (MIBI-TOF) and matrix-assisted laser desorption ionization
imaging (MALDI) we simultaneously visualize the composition, lineage, function and spatial distribution of tumor
and stromal cell populations and perform co-registered analysis of the glycome. We integrate these data within
the genomic landscape of metastatic disease and analyze these data within robust machine learning and
computational frameworks to uncover disease dynamics and features associated with clinical outcomes.
Lastly, we conduct genome-scale CRISPR screens in 3D breast cancer models to systematically define
oncogenic dependencies, therapeutic vulnerabilities and macrophage-tumor cell interactions.
This integrated systems biology and functional genomics approach will contribute to a quantitative and
mechanistic understanding of metastatic breast cancer and the dynamic relationship between tumor cells and
the host, with implications for therapeutic targeting.
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专著(0)
科研奖励(0)
会议论文
Admin-Core-001
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批准号:10707804
-
项目类别:
-
资助金额:$11.65万
-
财政年份:2022
-
负责人:Christina N Curtis
-
依托单位:
Project 1:Evolutionary dynamics and drivers of breast cancer metastasis and relapse
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批准号:10272389
-
项目类别:
-
资助金额:$26.33万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer
-
批准号:10704647
-
项目类别:
-
资助金额:$153.22万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Stanford Breast Metastasis Center Administrative Core
-
批准号:10272388
-
项目类别:
-
资助金额:$26.34万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer
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批准号:10272387
-
项目类别:
-
资助金额:$158.01万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Stanford Breast Metastasis Center Administrative Core
-
批准号:10704683
-
项目类别:
-
资助金额:$25.96万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Evolutionary dynamics and microenvironmental determinants of metastatic breast cancer
-
批准号:10660804
-
项目类别:
-
资助金额:$11.65万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Project 1:Evolutionary dynamics and drivers of breast cancer metastasis and relapse
-
批准号:10704684
-
项目类别:
-
资助金额:$33.86万
-
财政年份:2021
-
负责人:Christina N Curtis
-
依托单位:
Forecasting tumor evolution: can the past reveal the future?
-
批准号:10455013
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项目类别:
-
资助金额:$109.9万
-
财政年份:2018
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负责人:Christina N Curtis
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依托单位:
Forecasting tumor evolution: can the past reveal the future?
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批准号:10224138
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项目类别:
-
资助金额:$109.9万
-
财政年份:2018
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负责人:Christina N Curtis
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依托单位:
Organoid-based Discovery of Oncogenic Drivers and Treatment Resistance Mechanisms
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批准号:9751228
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项目类别:
-
资助金额:$91.8万
-
财政年份:2017
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负责人:Christina N Curtis
-
依托单位:
Organoid-based Discovery of Oncogenic Drivers and Treatment Resistance Mechanisms
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批准号:10219179
-
项目类别:
-
资助金额:$94.66万
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财政年份:2017
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负责人:Christina N Curtis
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依托单位:
Integrated genomic analysis and multi-scale modeling of therapeutic resistance
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批准号:8761828
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项目类别:
-
资助金额:$52.5万
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财政年份:2014
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负责人:Christina N Curtis
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依托单位:
海外基金