Endogenous Heterogeneity of Signaling Pathways in Cancer

癌症被经典地建模为具有致癌基因或肿瘤抑制基因的基因突变的恶性转化，其驱动不受控制的细胞生长。然而，这些基因表达水平的表观遗传或甚至随机内源性变化可能足以使增殖和凋亡途径失调，并驱动肿瘤发生。因此，可能存在癌症，其起源和维持源于正常途径的非遗传干扰。 在这个项目中，我们专注于慢性淋巴细胞白血病（CLL），一种淋巴组织增生性疾病，其特征是成熟B淋巴细胞在细胞周期的G 0/G1期停滞的克隆性扩增。到目前为止，还没有已知的突变赋予显性阳性或显性阴性活性的信号转导调节剂，这将解释细胞凋亡的抗性和增强的增殖的B细胞在CLL中。信号传导组分的差异表达（例如CDS和ZAP 70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的理解有限。 本研究的目的是研究慢性淋巴细胞白血病中维持增殖和凋亡的B细胞信号的异质性。为此，我们将引入一个系统生物学平台，该平台将B细胞信号传导的理论建模（在抗原、细胞因子或其他激活下）与单个原代细胞的实验测量相结合。更具体地说，我们计划依赖于B细胞的天然异质性（在CLL患者或健康个体中），以绘制出CLL疾病状态的变异性。我们将建立一个理论生化模型，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（从标志物到功能反应），以更好地表征CLL表型，并考虑到CLL B细胞的变异性，提供新的治疗方法。

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.