Elucidating the Relationship Between Cell Proliferation and Invasion

阐明细胞增殖与侵袭之间的关系

• 批准号: 10382255
• 负责人: Michael Adrian Martinez
• 金额: $ 3.9万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382255
• 关键词: Address; Alleles; Animals; Automobile Driving; Basement membrane; Behavior; Biological Phenomena; Breast; CDK4 gene; Caenorhabditis elegans; Cell Cycle; Cell Cycle Arrest; Cell Cycle Regulation; Cell Proliferation; Cell model; Cells; Cellular Structures; Clinical; Clinical Treatment; Clinical Trials; Data; Development; Down-Regulation; Event; FDA approved; FRAP1 gene; Fellowship; Future; G0 Phase; Genes; Goals; Homologous Gene; Human; In Vitro; Individual; Knowledge; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Metastatic breast cancer; Mission; Modeling; Molecular; Nematoda; Neoplasm Metastasis; Nuclear Hormone Receptors; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phenocopy; Process; Proliferating; Proteins; Public Health; Puncture procedure; Regulation; Research; Scientific Advances and Accomplishments; System; Techniques; Technology; Testing; Therapeutic; Uterus; Vulva; Work; base; cancer cell; cancer therapy; cell behavior; egg; high resolution imaging; imaging genetics; in vivo; in vivo Model; inhibitor; knock-down; mTOR inhibition; mutant; neoplastic cell; novel; preclinical study; prevent; senescence; sensor; therapy design; translational impact; treatment strategy; tumor growth

PROJECT SUMMARY/ABSTRACT Over the last five years, three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have been approved for the treatment of metastatic breast cancer. CDK4/6i prevent cancer cells from dividing by blocking their progression through the G1/G0 phase of the cell cycle. However, results from in vitro studies reveal that both exogenous and endogenous CDK4/6i increase the invasiveness of certain forms of cancer. The consequences of G1/G0 cell cycle arrest on cancer cell behavior in vivo remain unknown. Caenorhabditis elegans anchor cell (AC) invasion provides an excellent yet simple in vivo model of cell invasive behavior that allows single-cell and subcellular analysis of cell invasion through basement membrane. Our lab determined that G1/G0-specific arrest is required for AC invasion to occur and that the nuclear hormone receptor NHR-67/TLX acts as a key regulator of this process. In the absence of NHR-67, the AC becomes non-invasive but over-proliferates, indicating that proliferation can increase as invasion is blocked. The long-term goal is to understand both the molecular mechanisms controlling G1/G0 cell cycle arrest and the in vivo effects of CDK4/6i as individual agents and in combination with inhibitors of the mammalian target of rapamycin (mTORi). Together, CDK4/6i and mTORi have been shown to induce senescence in cancer cells in vitro, suggesting that combining these pharmacological agents might be useful in the clinical setting. The overall objectives of this fellowship application are to (i) elucidate how G1/G0 is maintained in the C. elegans AC and (ii) determine whether ACs in NHR-67-deficient animals can be pharmacologically induced to transition from proliferation-to-invasion-to-senescence. Based on preliminary data and prior research, the central hypothesis is that redundant mechanisms regulate the G1/G0 state of the wild-type AC and that proliferative ACs in NHR-67-deficient animals can be prompted to undergo senescence. This central hypothesis will be tested by pursuing two specifics aims. Aim 1 will identify the components regulating G1/G0 arrest in the pro-invasive AC. Aim 2 will evaluate the transition between AC proliferation, invasion and senescence upon depletion of CDK4/6, mTOR, or both. To address these aims, this project will use established gene knockdown techniques, high-resolution imaging, and cutting-edge technologies, including a novel live cell cycle state sensor and two conditional protein depletion systems. The results of these studies can help guide the development of future treatment strategies for aggressive cancers.

项目总结/摘要 在过去的五年中，三种细胞周期蛋白依赖性激酶4/6抑制剂（CDK 4/6 i）已被批准用于治疗癌症。 转移性乳腺癌的治疗。CDK 4/6 i通过阻断癌细胞的进展来防止癌细胞分裂 通过细胞周期的G1/G 0期。然而，体外研究的结果表明，外源性和 内源性CDK 4/6 i增加某些形式的癌症的侵袭性。G1/G 0细胞 周期阻滞对体内癌细胞行为的影响仍是未知的。秀丽隐杆线虫锚细胞（AC）侵袭 提供了一种优秀而简单的细胞侵入行为的体内模型， 通过基底膜的细胞侵袭分析。我们的实验室确定需要G1/G 0特异性阻滞 而核激素受体NHR-67/TLX是这一过程的关键调节因子 过程在没有NHR-67的情况下，AC变得非侵入性但过度增殖，表明 当侵袭被阻断时，增殖可以增加。长期目标是了解分子 控制G1/G 0细胞周期阻滞的机制和CDK 4/6 i作为单独药物的体内作用以及CDK 4/6 i在 与哺乳动物雷帕霉素靶点（mTORi）的抑制剂组合。CDK 4/6 i和mTORi共同具有 已经显示出在体外诱导癌细胞衰老，这表明将这些药理学物质结合在一起， 药物可能在临床环境中有用。本奖学金申请的总体目标是（i） 阐明G1/G 0在C中是如何维持的。和（ii）确定NHR-67缺陷型中的AC是否 动物可以被诱导从增殖到侵袭再到衰老的转变。基于 根据初步数据和先前的研究，中心假设是冗余机制调节G1/G 0 NHR-67缺陷型动物中的增殖性AC可被促使经历 衰老这一中心假设将通过追求两个具体目标来检验。目标1将确定 在促侵袭性AC中调节G1/G 0停滞的组分。目标2将评估AC和AC之间的过渡 CDK 4/6、mTOR或两者耗尽后的增殖、侵袭和衰老。为了实现这些目标， 该项目将使用成熟的基因敲除技术，高分辨率成像和尖端的 技术，包括一种新的活细胞周期状态传感器和两个条件蛋白质消耗系统。的 这些研究的结果可以帮助指导未来发展侵袭性癌症的治疗策略。