Endogenous Heterogeneity of Signaling Pathways in Cancer

癌症信号通路的内源异质性

• 批准号: 8468148
• 负责人: Gregoire Altan-Bonnet
• 金额: $ 41.91万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8468148
• 关键词: Accounting; Antigens; Apoptosis; Automobile Driving; B Cell Proliferation; B-Lymphocytes; Biochemical; Biological Assay; Blocking Antibodies; Cell Cycle; Cell Survival; Cells; Cessation of life; Characteristics; Chronic Lymphocytic Leukemia; Clinical; Clonal Expansion; Computer Simulation; Custom; Data; Diagnostic; Disease; Disease Progression; Dominant-Negative Mutation; Epigenetic Process; G1 Phase; Gene Mutation; Genes; Goals; Growth; Heterogeneity; Human; In Vitro; Individual; Lymphoproliferative Disorders; Maintenance; Malignant - descriptor; Malignant Neoplasms; Maps; Mature B-Lymphocyte; Measurement; Measures; Methodology; Modeling; Mutation; Oncogenes; Pathway interactions; Patients; Phenotype; Population; Research Project Grants; Resistance; Signal Pathway; Signal Transduction; Signaling Protein; Stimulus; Stromal Cells; System; Systems Biology; Testing; Theoretical model; Tumor Suppressor Genes; Up-Regulation; Variant; base; biochemical model; cell growth; computerized data processing; crosslink; cytokine; molecular marker; non-genetic; novel therapeutic intervention; receptor; response; stem; therapeutic target; tool; tumorigenesis

Cancer is classically modeled as a malignant transformation with genetic mutation of oncogenes or tumor suppressor genes driving uncontrolled cellular growth. However, epigenetic or even stochastic endogenous variations in the expression levels of these genes may be sufficient to disregulate proliferation and apoptosis pathways, and drive tumorigenesis. Thus, there may exist cancers whose origin and maintenance stem from non-genetic perturbations of normal pathways. In this project, we focus on Chronic Lymphocytic Leukemia (CLL), a lymphoproliferative disease characterized by the clonal expansion of mature B lymphocytes arrested in the G0/G1 phase of the cell cycle. To date, there is no known mutation conferring dominant-positive or dominant negative activities to signaling regulators that would account for the resistance to apoptosis and enhanced proliferation of B cells in CLL. Differential expression of signaling components (e.g. upregulation of CDS and ZAP70) is used to predict clinical prospects for CLL patients, but there is limited understanding of their relevance to the growth dysregulation and disease progression. The goal of this research project is to study the heterogeneity of B cell signaling sustaining proliferation and apoptosis in CLL. For that purpose, we will introduce a systems biology platform that combines theoretical modeling of B cell signaling (under activation by antigens, cytokines or others) with experimental measurements on single primary cells. More specifically, we plan to rely on the natural heterogeneity of B cells (in CLL patients or in healthy individuals), to map out the variability of CLL disease states. We will develop a theoretical biochemical model, to identify key signaling regulators in B cell signaling. We will also apply a new experimental methodology to correlate, at the single cell level, B cell responsiveness with expression levels of these key signaling regulators. Ultimately, we aim at introducing multivariate parameters of individual cells within a population (from markers to functional response) to better characterize CLL phenotypes and offer new therapeutic approaches taking into account the variability in CLL B cells.

癌症通常被建模为癌基因或肿瘤抑制基因的基因突变驱动不受控制的细胞生长的恶性转化。然而，这些基因表达水平的表观遗传甚至随机内源性变化可能足以失调增殖和凋亡途径，并驱动肿瘤发生。因此，可能存在其起源和维持源于正常途径的非遗传扰动的癌症。 在这个项目中，我们重点关注慢性淋巴细胞白血病 (CLL)，这是一种淋巴组织增生性疾病，其特征是停滞在细胞周期 G0/G1 期的成熟 B 淋巴细胞的克隆性扩张。迄今为止，尚无已知的突变赋予信号调节因子显性阳性或显性阴性活性，从而解释 CLL 中 B 细胞对细胞凋亡的抵抗和增殖的增强。信号成分的差异表达（例如 CDS 和 ZAP70 的上调）用于预测 CLL 患者的临床前景，但对其与生长失调和疾病进展的相关性了解有限。 该研究项目的目标是研究 CLL 中维持增殖和凋亡的 B 细胞信号传导的异质性。为此，我们将引入一个系统生物学平台，该平台将 B 细胞信号传导（在抗原、细胞因子或其他物质激活下）的理论模型与单个原代细胞的实验测量相结合。更具体地说，我们计划依靠 B 细胞（CLL 患者或健康个体）的自然异质性来绘制 CLL 疾病状态的变异性。我们将开发一个理论生化模型，以确定 B 细胞信号传导中的关键信号调节因子。我们还将应用一种新的实验方法，在单细胞水平上将 B 细胞反应性与这些关键信号调节因子的表达水平相关联。最终，我们的目标是引入群体内单个细胞的多变量参数（从标记物到功能反应），以更好地表征 CLL 表型，并考虑 CLL B 细胞的变异性提供新的治疗方法。