Elucidating connections between anastasis and cancer drug resistance

阐明吻合与癌症耐药性之间的联系

基本信息

批准号：
10056879
负责人：
Ho Lam Tang
金额：
$ 41.11万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056879
关键词：
Abnormal Cell Adverse event Aftercare Agar Anchorage-Independent Growth Antineoplastic Agents Apoptosis Apoptosis Promoter Apoptotic Autophagocytosis Biological Process Brain Injuries Cancer Relapse Cancer cell line Caspase Cell Death Cell Fraction Cell Survival Cell division Cells Cessation of life Chromosome abnormality Chromosomes Clinical Clinical Management Contact Inhibition Cytosol DNA Damage Degenerative Disorder Disease Dose Drug resistance Evolution Exposure to Fluorescent in Situ Hybridization Frequencies Greek Growth Heart failure Hepatocyte Heterogeneity Human Induction of Apoptosis Intuition Karyotype determination procedure Lead Life Light Malignant Neoplasms Maps Mitochondria Molecular Abnormality Mutagenesis Mutation Names Normal Cell Nuclear Oncogenic Pathologic Pathway interactions Phenotype Physical condensation Process Radial Recovery Recurrence Recurrent Malignant Neoplasm Recurrent tumor Resistance Resistance development Role Stimulus Testing Therapeutic Time Treatment Failure Variant cancer cell cancer drug resistance cancer recurrence cancer therapy cancer type carcinogenicity cell suicide cell type cytochrome c daughter cell drug development live cell microscopy neoplastic cell new therapeutic target novel strategies response therapeutic target tumor tumor progression tumorigenesis

项目摘要

Project Summary Activating programmed cell death such as apoptosis is one of the most important therapeutic strategies for cancer therapy. Many cancers undergo dramatic initial responses to such therapy. However, cancer relapse with the development of drug resistance is a major problem in the clinical management of most types of cancer, leading to treatment failure. The classical view of cell death has long assumed that, once initiated, the apoptotic dying process is irreversible. However, we discovered that dying cancer cells and primary cells can reverse the apoptotic process even at late execution stages, and named this cell recovery mechanism Anastasis (Greek for “rising to life”). The discovery of anastasis suggests an unexpected tactic that cancer cells could use to escape cell death-inducing cancer therapy. Central to this proposal, we have demonstrated that some cells acquired permanent genetic changes during anastasis and undergo oncogenic transformation at a higher frequency than controls. Moreover, anastatic cells display an increased resistance to apoptotic stimuli such as anticancer drugs. These observations lead to an intriguing question: Can anastasis contribute to the development of drug resistance in recurrent tumors? If so, anastasis would be a potential and novel therapeutic target for suppressing cancer progression and recurrence. Since mutations contribute to the development of resistance, we propose that cancer cell survival by anastasis occurring at the interval between cycles of anticancer therapy could allow apoptosis-caused DNA damage to be perpetuated and lead to mutagenesis, progression, and evolution of drug resistance in recurrent cancers. In Specific Aim 1, we propose to test for and identify such mutations if they occur, and determine whether mutational hotspots exist in anastatic cells. We will then compare any mutations identified with the known mutational signatures that have been mapped in recurrent clinical tumors. This will directly test for connections between anastasis and mutagenesis in cancer cells. In Specific Aim 2, we propose to compare the sensitivity of anastatic cancer cells to different cell death inducers. Anastatic cells that have recovered from repeated inductions of apoptosis often develop resistance to the same cell death stimulus. However, it is not known whether these anastatic cells might also be resistant to other cell death inducers. We will test for this possibility by determining whether anastasis increases resistance of cancer cells to higher doses of the same inducer, and may also result in “cross-resistance” to other pathways of cell death, e.g., autophagy, ferroptosis, and necroptosis. Overall, these studies seek to elucidate connections between anastasis and development of drug resistance in cancer cells that can be targeted and useful in new approaches to anticancer therapy.

项目概要激活程序性细胞死亡（例如细胞凋亡）是最重要的治疗策略之一许多癌症对这种治疗有显着的初始反应。随着耐药性的发展而复发是大多数临床管理中的一个主要问题细胞死亡的经典观点长期以来一直认为，一旦启动，细胞凋亡的死亡过程是不可逆转的。然而，我们发现死亡的癌症。细胞和原代细胞即使在执行后期也能逆转凋亡过程，并将其命名为细胞恢复机制 Anastasis（希腊语“复活”） Anastasis 的发现表明了一种机制。癌细胞可以利用这种意想不到的策略来逃避诱导细胞死亡的癌症治疗。根据这项提议，我们已经证明一些细胞在吻合并以比对照更高的频率发生致癌转化。突变细胞对抗癌药物等凋亡刺激的抵抗力增强。观察结果引出了一个有趣的问题：anastasis 能否有助于药物的开发如果是的话，anastasis 将是一个潜在的新治疗靶点抑制癌症进展和复发。抗性，我们建议癌细胞通过吻合发生在周期之间的间隔内存活抗癌治疗可能会使细胞凋亡引起的 DNA 损伤持续存在，并导致在特定目标 1 中，我们研究了复发性癌症的突变、进展和耐药性进化。建议测试并识别此类突变（如果发生），并确定是否存在突变热点然后，我们将比较任何已识别的突变与已知的突变。已在复发性临床肿瘤中绘制的特征这将直接测试连接。在具体目标 2 中，我们建议比较癌细胞的突变和突变。变性癌细胞对已恢复的变性细胞死亡诱导剂的敏感性。然而，反复诱导细胞凋亡通常会产生对相同细胞死亡刺激的抵抗力。目前尚不清楚这些细胞是否也对其他细胞死亡诱导剂具有抵抗力。通过确定 anastasis 是否增加癌细胞对更高的抵抗力来测试这种可能性同一诱导剂的剂量，也可能导致对其他细胞死亡途径的“交叉耐药”，例如，总的来说，这些研究试图阐明自噬、铁死亡和坏死性凋亡之间的联系。癌细胞中耐药性的分析和发展可以作为新的目标并有用抗癌治疗的方法。