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Delineating the dystopian nature of the cell cycle in cancer

描绘癌症细胞周期的反乌托邦性质

基本信息

批准号：
10634518
负责人：
Erik Knudsen
金额：
$ 53.84万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-03 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634518
关键词：
Ablation Automobile Driving Biochemical Biological Breast Cancer cell line CCNE1 gene CDK4 gene Cancer Model Cancer cell line Cell Cycle Cell Cycle Deregulation Cell Cycle Progression Cell Cycle Regulation Cells Clinic Complex Computer Models Coupled Cyclin D1 Cyclins Data Dependence Disparate Event Evolution FDA approved Foundations G1 Phase Gene Expression Genes Heterogeneity Intervention Lead Malignant Neoplasms Mammalian Cell Modeling Molecular Nature Oncogenes Oncogenic Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Primary Neoplasm Process Proliferating Resistance Role Signal Transduction Specimen Therapeutic Therapeutic Intervention Tissues Tumor Tissue Work Xenograft procedure cancer cell clinically relevant clinically significant in vivo inhibitor malignant breast neoplasm novel strategies oncogene addiction pharmacologic response targeted treatment therapeutic target therapy resistant tool triple-negative invasive breast carcinoma tumor tumorigenic

项目摘要

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.

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物负责以顺序方式驱动特定事件。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物。这些复合物促进 RB 磷酸化，从而导致高度保守的基因核心的表达，这些基因是在剩余的过程中进展所必需的细胞周期。该模型提出的概念是细胞周期控制是线性的且高度可预测的。然而，最近与 CDK/细胞周期蛋白相互依赖性相关的发现表明需要更好的方法了解在肿瘤中可操作的细胞周期库。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”简单版本的程度崩溃。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，对于致瘤性增殖和治疗干预具有重要意义。这里我们将综合考虑从根本上理解“反乌托邦”细胞周期状态（目标 1）并定义附带机制的方法与非规范细胞周期状态相关的治疗耐药性和新的脆弱性（目标 2）。