Understanding and targeting the DNA replication stress in cancer cells

了解并针对癌细胞中的 DNA 复制压力

基本信息

批准号：
10813321
负责人：
Lee Zou
金额：
$ 94.63万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-24 至 2028-06-30
项目状态：
未结题

项目摘要

Project Summary DNA replication problems collectively known as replication stress are a major sources of genomic instability in cancer cells and also a vulnerability of cancer that can be targeted therapeutically. The recent success of PARP inhibitors in the treatment of BRCA mutant tumors provided an exciting example of targeting cancer cells by exploiting replication stress. However, our current understanding of the replication stress in cancer cells is still very limited. Although we know that many different oncogenic events in cancer cells can cause replication problems, we still don't fully understand whether these oncogenic events affect DNA replication in similar or distinct ways. Furthermore, we also know little about how DNA replication is altered by different oncogenic events, and whether altered replication can give rise to distinct cellular vulnerabilities. Understanding the basic molecular features of replication stress, the major causes of replication stress in cancer cells, and the different vulnerabilities resulting from altered replication will greatly enhance our ability to detect and exploit replication stress in cancer therapy. I have a longstanding interest in understanding the replication stress response in human cells. In particular, my lab has extensively studied the functions and regulation of the ATR checkpoint pathway, the master regulator of replication stress response in human cells. Our work has contributed significantly to the current models of stress sensing and signaling during DNA replication. From recent studies by us and others, it has become gradually clear that different oncogenic events in cancer cells can generate distinct problems in DNA replication. Furthermore, RNA transcripts, the products of transcription, have both positive and negative impacts on DNA replication and repair. Our studies also revealed that replication stress not only exerts cell autonomous effects on the genome, but also cell non-autonomous effects in cell populations. Based on these new findings, we propose to systematically define and characterize different types of replication stress in cancer cells, understand how RNA affects replication and repair in the genome, and explore the cell non-autonomous effects of replication stress in tumor microenvironments and cancer therapy. These studies may provide us a much more comprehensive understanding of the molecular underpinnings of replication stress in cancer cells, their impacts on the genome of cancer cells and cell populations in tumor microenvironments, and the cancer cell-specific vulnerabilities that they give rise to. The new concepts and findings from these studies could have transformative impacts on the research of cancer and cancer therapy.

项目概要 DNA 复制问题统称为复制应激，是基因组不稳定的主要来源。癌细胞以及可以进行靶向治疗的癌症的脆弱性。 PARP 最近的成功抑制剂在治疗 BRCA 突变肿瘤中提供了一个令人兴奋的靶向癌细胞的例子利用复制压力。然而，我们目前对癌细胞复制应激的理解仍然不明确。非常有限。尽管我们知道癌细胞中许多不同的致癌事件都会导致复制问题，我们仍然不完全了解这些致癌事件是否会影响类似或类似的 DNA 复制不同的方式。此外，我们对不同致癌基因如何改变 DNA 复制也知之甚少。事件，以及复制的改变是否会导致不同的细胞脆弱性。了解基本知识复制应激的分子特征、癌细胞复制应激的主要原因以及不同的复制应激复制更改导致的漏洞将大大增强我们检测和利用复制的能力癌症治疗中的压力。我长期以来对了解人类细胞的复制应激反应很感兴趣。特别是我的实验室广泛研究了 ATR 检查点通路的功能和调节，ATR 检查点通路是人类细胞的复制应激反应。我们的工作对当前的压力模型做出了重大贡献 DNA 复制过程中的传感和信号传导。从我们和其他人最近的研究来看，它已经逐渐变得很明显，癌细胞中不同的致癌事件会在 DNA 复制中产生不同的问题。此外，RNA转录物（转录产物）对DNA既有积极的影响，也有消极的影响复制和修复。我们的研究还表明，复制压力不仅会产生细胞自主效应对基因组的影响，而且对细胞群体的细胞非自主效应也有影响。基于这些新发现，我们提议系统地定义和表征癌细胞中不同类型的复制应激，了解 RNA如何影响基因组的复制和修复，并探索复制的细胞非自主效应肿瘤微环境和癌症治疗中的压力。这些研究可能为我们提供更多信息全面了解癌细胞复制应激的分子基础及其影响肿瘤微环境中癌细胞和细胞群的基因组以及癌细胞特异性它们引起的漏洞。这些研究的新概念和发现可能具有变革性对癌症和癌症治疗研究的影响。