Single-Cell, Spatial and Functional Dissection of Cancer Cell States, Co-Evolving Ecosystems, and Vulnerabilities During Tumor Progression and Metastasis

癌细胞状态、共同进化生态系统以及肿瘤进展和转移过程中的脆弱性的单细胞、空间和功能剖析

基本信息

  • 批准号:
    10729386
  • 负责人:
  • 金额:
    $ 38.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-19 至 2028-08-31
  • 项目状态:
    未结题

项目摘要

Aggressive cancers often lack pharmacologically actionable mutations and do not respond to immune checkpoint blockade, thus deriving only modest clinical benefit from targeted and immune therapy. The heterogeneity of both transformed and healthy cells in the Tumor Microenvironment (TME) represents a critical obstacle to achieving more durable response in cancer patients. Recent insights, using multi-omics approaches, have shown that cancer cells can exist in a variety of transcriptionally distinct, yet co-existing states, some of which are already primed for metastatic progression or drug resistance. The plasticity of these states—i.e., the ability of cancer cells to reprogram across multiple states, either spontaneously or because of drug perturbations—and their homeostatic coexistence with other TME subpopulation, via paracrine molecular interactions, creates a constant challenge to therapeutic approaches by fostering the emergence of drug-resistance, tumor progression, and the creation of a pro-malignant, immunosuppressive milieu. Malignant states and transitions are only partially explained by sequential acquisition of somatic mutations, suggesting that they result from integration of a variety of cell-intrinsic and -extrinsic molecular cues that determine their lineage attribution, establishment, and interconversion. To date, several technical, clinical, and analytical challenges have hampered a comprehensive understanding of the natural biology of these processes in patients. Project 2 is dedicated to resolving the variability and plasticity of malignant cells and of the healthy cells that define the TME by developing and applying a battery of technical and analytical tools for the dissection of cancer heterogeneity at the single-cell level, and for the nomination, validation and testing of novel drivers of tumor-progression and therapy response and resistance. We will delineate these concepts in a defined biological context, that is the progression from a primary tumor towards brain-metastatic disease. To this end, we will leverage a series of innovations from CaST investigators, including (a) multi-modal single-cell profiling from archival tissues, (b) simultaneous low-pass whole-genome sequencing (lpWGS) of the same cell pool, (c) integrated single-cell and spatial single-cell transcriptomics, (d) analytical approaches to integrate and model multi-modal single-cell data in space, time and context of interactions among cells, (e) tools to elucidate cell state stability and transitions, (f) combinations of genome-editing perturbations with single-cell read outs that can be linked to drug screens via gene expression profiling, and (g) network-based Master Regulator analyses to elucidate mechanistic determinants of transcriptional cell state. This will be extended by experimental innovations, that (h) accurately model tumor progression in vivo and recapitulate entire human ecosystems, (i) enable labeling of metastatic niches coupled with single-cell genomics, and (j) provide a platform to test pharmacological modulation of cancer cell intrinsic and tumor-microenvironmental features predicted from human studies and modeling. The presented innovative framework will be broadly application to other cancer contexts.
侵袭性癌症通常缺乏药理上可操作的突变,并且对免疫检查点没有反应。 阻断,因此从靶向和免疫治疗中只能获得不大的临床益处。的异构性 肿瘤微环境(TME)中的转化细胞和健康细胞都是 在癌症患者中实现更持久的反应。使用多组学方法的最新见解表明, 癌细胞可以以多种转录上不同但共存的状态存在,其中一些是 已经为转移进展或抗药性做好了准备。这些状态的可塑性--即 癌细胞跨越多个状态重新编程,要么是自发的,要么是因为药物扰动--以及 通过旁分泌分子相互作用,他们与其他TME亚群的动态平衡共存创造了一个 不断挑战治疗方法,促进耐药性的出现,肿瘤的进展, 以及创造一个有利于恶性的、免疫抑制的环境。恶性状态和转变只是部分 用体细胞突变的顺序获取来解释的,这表明它们是一种多样性整合的结果 决定它们的谱系归属、建立和发展的细胞内在和外在分子线索 相互转换。到目前为止,几个技术、临床和分析挑战阻碍了全面的 了解患者体内这些过程的自然生物学。项目2致力于解决 通过开发和应用确定TME的恶性细胞和健康细胞的可变性和可塑性 一系列技术和分析工具,用于在单细胞水平上剖析癌症的异质性,以及 提名、验证和测试肿瘤进展和治疗反应的新驱动因素 抵抗。我们将在定义的生物学背景下描述这些概念,即从初级到高级 肿瘤向脑转移疾病发展。为此,我们将利用CAST的一系列创新 调查人员,包括(A)档案组织的多模式单细胞分析,(B)同时低通 同一细胞池的全基因组测序(LPWGS),(C)集成单细胞和空间单细胞 转录学,(D)对空间、时间和空间的多模式单细胞数据进行整合和建模的分析方法 细胞间相互作用的背景,(E)阐明细胞状态稳定性和转变的工具,(F)组合 可通过基因表达与药物筛选相关联的单细胞读出的基因组编辑扰动 分析,和(G)基于网络的主调节器分析,以阐明 转录细胞状态。这将通过实验创新得到扩展,即(H)准确地建立肿瘤模型 体内进展和概括整个人类生态系统,(I)能够标记耦合的转移生态位 单细胞基因组学,以及(J)提供了一个测试癌细胞内在药理调节的平台 以及从人体研究和建模中预测的肿瘤微环境特征。展示的创新 该框架将被广泛应用于其他癌症背景。

项目成果

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Benjamin Izar其他文献

Benjamin Izar的其他文献

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{{ truncateString('Benjamin Izar', 18)}}的其他基金

Multi-cellular interactions defining the human brain metastatic niche
多细胞相互作用定义人脑转移生态位
  • 批准号:
    10651257
  • 财政年份:
    2023
  • 资助金额:
    $ 38.49万
  • 项目类别:
The role of the CD58:CD2 axis in cancer immune evasion and resistance to immunotherapy
CD58:CD2轴在癌症免疫逃避和免疫治疗抵抗中的作用
  • 批准号:
    10671582
  • 财政年份:
    2022
  • 资助金额:
    $ 38.49万
  • 项目类别:
Dissecting drug resistance in serial uveal melanoma biopsies using integrated, multi-modal single-cell profiling and novel machine learning tools.
使用集成的多模式单细胞分析和新颖的机器学习工具剖析连续葡萄膜黑色素瘤活检中的耐药性。
  • 批准号:
    10290692
  • 财政年份:
    2021
  • 资助金额:
    $ 38.49万
  • 项目类别:
Mechanisms of liver metastasis and associated resistance to immunotherapy
肝转移的机制和相关的免疫治疗耐药性
  • 批准号:
    10818003
  • 财政年份:
    2021
  • 资助金额:
    $ 38.49万
  • 项目类别:
Mechanisms of liver metastasis and associated resistance to immunotherapy
肝转移的机制和相关的免疫治疗耐药性
  • 批准号:
    10368974
  • 财政年份:
    2021
  • 资助金额:
    $ 38.49万
  • 项目类别:
Mechanisms of liver metastasis and associated resistance to immunotherapy
肝转移的机制和相关的免疫治疗耐药性
  • 批准号:
    10593044
  • 财政年份:
    2021
  • 资助金额:
    $ 38.49万
  • 项目类别:
Mechanisms of liver metastasis and associated resistance to immunotherapy
肝转移的机制和相关的免疫治疗耐药性
  • 批准号:
    10185418
  • 财政年份:
    2021
  • 资助金额:
    $ 38.49万
  • 项目类别:
Dissecting drug resistance in serial uveal melanoma biopsies using integrated, multi-modal single-cell profiling and novel machine learning tools.
使用集成的多模式单细胞分析和新颖的机器学习工具剖析连续葡萄膜黑色素瘤活检中的耐药性。
  • 批准号:
    10447792
  • 财政年份:
    2021
  • 资助金额:
    $ 38.49万
  • 项目类别:
Dissecting mechanisms of immunotherapy resistance in melanoma patients
剖析黑色素瘤患者免疫治疗耐药的机制
  • 批准号:
    10231195
  • 财政年份:
    2017
  • 资助金额:
    $ 38.49万
  • 项目类别:
Dissecting mechanisms of immunotherapy resistance in melanoma patients
剖析黑色素瘤患者免疫治疗耐药的机制
  • 批准号:
    9751820
  • 财政年份:
    2017
  • 资助金额:
    $ 38.49万
  • 项目类别:

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具有变构结合行为的多重连接的穴状配体分子的开发
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