Delineating the dystopian nature of the cell cycle in cancer

摘要：在经典的哺乳动物细胞周期模型中，CDK和细胞周期蛋白复合体负责 以连续的方式驱动特定的事件。有丝分裂或致癌信号驱动CDK4/6的激活 启动细胞周期进程的复合体。这些络合物促进Rb的磷酸化，从而导致 高度保守的一组基因的表达，这些基因是通过其余部分的过程所需的 细胞周期。这个模型提出的概念是，细胞周期控制是线性的，具有很高的可预测性。 然而，最近有关CDK/Cyclins相互依赖关系的发现表明，有必要更好地 了解肿瘤中可操作的细胞周期谱系。在初步数据中使用无偏和 有针对性的方法我们已经询问了细胞周期的“乌托邦”简单版本在多大程度上 崩溃-崩溃。这项工作表明，在癌症模型中，存在多种不同的细胞周期模式，其中 对肿瘤的增殖和治疗干预具有重要意义。在这里，我们将采取一个综合的 从根本上理解“反乌托邦”细胞周期状态的方法(目标1)和定义侧支机制 与非规范细胞周期状态相关的治疗耐药和新的脆弱性(目标2)。

ABSTRACT: In the classical mammalian cell cycle model, CDK and cyclin complexes are responsible for driving specific events in a sequential fashion. Mitogenic or oncogenic signals drive the activation of CDK4/6 complexes that initiate cell cycle progression. These complexes promote RB phosphorylation that leads to the expression of a highly conserved cadre of genes that are required for progression through the remainder of the cell cycle. The concept put forward by this model is that cell cycle control is linear and highly predictable. However, recent findings related to the inter-dependencies of CDK/cyclins illustrate the need for better understanding the cell cycle repertoires that are operable in tumors. In preliminary data using unbiased and targeted approaches we have interrogated the extent to which the “utopian” simple version of the cell cycle breaks-down. This work indicates that in cancer models there are multiple different cell cycle modes, which have significance for tumorigenic proliferation and therapeutic interventions. Here we will take an integrated approach to fundamentally understand “dystopian” cell cycle states (Aim 1) and define mechanisms of collateral therapeutic resistance and new vulnerabilities (Aim 2) which associate with non-canonical cell cycle states.