Endogenous Heterogeneity of Signaling Pathways in Cancer

癌症的经典模型是癌基因或抑癌基因突变引起的恶性转化 控制细胞生长的基因然而，后天的，甚至是随机的内源性， 这些基因表达水平的变化可能足以使增殖和凋亡失调 通路，并驱动肿瘤发生。因此，可能存在癌症，其起源和维持源于 正常途径的非基因干扰。 在这个项目中，我们专注于慢性淋巴细胞白血病（CLL），一种淋巴增生性疾病， 通过阻滞在细胞周期G 0/G1期的成熟B淋巴细胞的克隆扩增。迄今为止 没有已知的突变赋予信号调节因子显性阳性或显性阴性活性， 可能是导致慢性淋巴细胞白血病B细胞凋亡抵抗和增殖增强的原因。差分 信号传导组分的表达（例如CDS和ZAP 70的上调）用于预测临床前景 对于CLL患者，但对其与生长失调和疾病的相关性的了解有限 进展 本研究项目的目标是研究维持增殖的B细胞信号传导的异质性， CLL中的细胞凋亡。为此，我们将介绍一个系统生物学平台， 用实验方法模拟B细胞信号传导（在抗原、细胞因子或其它激活下） 对单个原电池进行测量。更具体地说，我们计划依靠B细胞的天然异质性 (in CLL患者或健康个体中），以绘制出CLL疾病状态的可变性。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剂。我们还将采用新的 在单细胞水平上，将B细胞反应性与 这些关键的信号调节器。最后，我们的目标是引入单个细胞的多变量参数 在人群中（从标志物到功能反应），以更好地表征CLL表型，并提供新的 考虑到CLL B细胞的可变性的治疗方法。

Cancer is classically modeled as a malignant transformation with genetic mutation of oncogenes or tumorsuppressor genes driving uncontrolled cellular growth. However, epigenefic or even stochasfic 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-genefic perturbafions 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 mutafion conferring dominant-positive or dominant negative activifies to signaling regulators that would account for the resistance to apoptosis and enhanced proliferafion of B cells in CLL. Differenfial 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 pafients or in healthy individuals), to map out the variability of CLL disease states. We will develop a theorefical 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. Ulfimately, 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 therapeufic approaches taking into account the variability in CLL B cells.