Therapeutic Management of Lineage- and Differentiation-state Plasticity

谱系和分化状态可塑性的治疗管理

• 批准号: 10166788
• 负责人: ROSALIE C SEARS
• 金额: $ 40.73万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166788
• 关键词: ATAC-seq; Address; Aftercare; Automobile Driving; Bar Codes; Breast Cancer Cell; Breast Cancer cell line; Cell model; Cell physiology; Cells; Cessation of life; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Combined Modality Therapy; Computer Models; Data; Dependence; Disease; Disease Progression; Disease Resistance; Drug Combinations; Drug resistance; Epigenetic Process; Event; Genetic; Genotype; Goals; Heterogeneity; Image; Image Cytometry; In Vitro; Libraries; Link; Malignant Neoplasms; Maps; Measures; Mediating; Mesenchymal; Mesenchymal Differentiation; Metadata; Modeling; Molecular; Oncogenic; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Population; Population Heterogeneity; Proteins; Recurrence; Regulation; Regulatory Element; Residual state; Resistance; Route; Systems Biology; Testing; Therapeutic; Time; Treatment Efficacy; Work; Xenograft procedure; analytical method; base; cancer cell; clinically relevant; combinatorial; computer framework; differential expression; drug efficacy; epigenetic regulation; experimental study; in vivo; inhibitor/antagonist; live cell imaging; malignant breast neoplasm; molecular modeling; neoplastic cell; novel therapeutics; outreach; population based; prevent; response; single-cell RNA sequencing; targeted treatment; therapy resistant; transcriptome sequencing; treatment response; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity

ABSTRACT – Project 1 Intratumoral heterogeneity is a major cause of therapeutic resistance in breast cancer. Studies have demonstrated that a subset of cancer cells within a heterogeneous tumor can escape therapy-induced death due to innate or adaptive resistance, resulting in recurrence, disease progression, and poor patient survival. Triple negative breast cancer (TNBC) is an aggressive disease characterized by high intratumor heterogeneity and poor patient outcome. In preliminary experiments, we identified subpopulations of tumor cells in primary TNBC as well as in basal-like TNBC cell lines that are characterized by differential expression of luminal, basal, and mesenchymal differentiation-state markers. We have observed that distinct classes of targeted therapeutics have the capacity to eliminate or enrich specific differentiation-state subpopulations within these lines, steering heterogeneous cancer cell populations toward increased homogeneity. Importantly, we identified synergistic combinatorial treatments that targeted either pathway dependencies predicted by master regulator analysis of residual cells or epigenetic regulators found to contribute to a cell's transition to a resistant state. The overall goal of this project, therefore, is to understand cell intrinsic regulation of therapeutic response in phenotypically heterogeneous TNBC in order to develop targeting strategies to kill all co-existing subpopulations. We focus on phenotypic heterogeneity, as this can represent the combination of genetic and epigenetic factors, and we will take advantage of clinically relevant therapeutics that drive heterogeneous populations toward homogeneity. We hypothesize that a systems biology approach of measuring and computationally modeling the functional pathways underlying phenotypic state changes in response to state-aggregating therapeutics will reveal common escape routes and regulators of cell plasticity, which will allow us to predict effective combinatorial therapeutic strategies that eliminate all cancer subpopulations. We will address this hypothesis by (1) examining and computationally modeling phenotype state changes in multiple genetically diverse, heterogeneous TNBC cell lines in response to targeted therapeutics that induce homogeneity using high-content imaging and single cell expression analysis, (2) determining whether clonal expansion or differentiation state plasticity drives the dynamic phenotype changes following targeted therapy and modeling the molecular network changes that underlie these transitions, and (3) determining epigenetic regulation underlying state transitions and developing combinatorial strategies that overcome therapeutic resistance in heterogeneous TNBC cells in vitro and in vivo. Together, these aims support our goal to measure and model cell intrinsic responses to clinically relevant targeted therapeutics and to predict synergistic drug combinations that more effectively control heterogeneous TNBC. Integration of this work with Projects 2 and 3 in the M2CH-CSBC will allow us to incorporate extrinsic regulators of these intrinsic mechanisms and to iteratively refine control strategies for this devastating disease. !

摘要 – 项目 1 瘤内异质性是乳腺癌治疗耐药的主要原因。研究有 证明异质肿瘤内的一部分癌细胞可以逃避治疗引起的死亡 由于先天性或适应性抵抗，导致复发、疾病进展和患者生存率低下。 三阴性乳腺癌（TNBC）是一种侵袭性疾病，其特点是肿瘤内异质性高 和患者预后不佳。在初步实验中，我们鉴定了原代细胞中的肿瘤细胞亚群 TNBC 以及类似基底的 TNBC 细胞系，其特征是腔、基底、 和间充质分化状态标记。我们观察到不同类别的目标 治疗有能力消除或丰富这些特定的分化状态亚群 线，引导异质癌细胞群趋于增加同质性。重要的是，我们确定了 针对主调节器预测的任一途径依赖性的协同组合治疗 对残留细胞或表观遗传调节因子的分析发现有助于细胞向耐药状态的转变。 因此，该项目的总体目标是了解细胞对治疗反应的内在调节 表型异质 TNBC，以制定杀死所有共存的靶向策略 亚人群。我们关注表型异质性，因为这可以代表遗传和 表观遗传因素，我们将利用临床相关的疗法来驱动异质性 人口走向同质化。我们假设一种系统生物学方法可以测量和 对反应中表型状态变化的功能途径进行计算建模 状态聚合疗法将揭示细胞可塑性的常见逃逸途径和调节因子， 这将使我们能够预测消除所有癌症的有效组合治疗策略 亚人群。我们将通过（1）检查和计算表型模型来解决这个假设 多种遗传多样性、异质性 TNBC 细胞系响应靶向药物的状态变化 使用高内涵成像和单细胞表达分析诱导同质性的疗法，(2) 确定克隆扩张或分化状态可塑性是否驱动动态表型变化 进行靶向治疗并对这些转变背后的分子网络变化进行建模，以及 (3) 确定状态转变背后的表观遗传调控并制定组合策略 克服异质 TNBC 细胞在体外和体内的治疗耐药性。这些目标共同实现 支持我们测量和模拟细胞对临床相关靶向治疗的内在反应的目标 预测更有效控制异质 TNBC 的协同药物组合。整合这个 与 M2CH-CSBC 中的项目 2 和 3 合作将使我们能够将这些内在的外在调节器纳入其中 机制并迭代完善针对这种毁灭性疾病的控制策略。 ！