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Cell survival by anastasis, a novel therapeutic target in cancer

细胞存活通过吻合，癌症的新治疗靶点

基本信息

批准号：
9751798
负责人：
Ho Lam Tang
金额：
$ 16.2万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751798
关键词：
Aftercare Agar Animals Apoptosis Apoptosis Promoter Apoptotic Bioinformatics Biological Assay Biosensor CASP3 gene Cancer cell line Caspase Cell Death Cell Survival Cell membrane Cell surface Cells Cellular Morphology Cervix carcinoma Cessation of life Chromatin Chromosomes Clinical Management Cytosol DNA Damage Dangerousness Development Disseminated Malignant Neoplasm Drosophila genus Drosophila melanogaster Exhibits Female Fibroblasts Frequencies Future Germ Cells Goals Greek Growth Hela Cells HepG2 Hepatocyte Homeostasis Human Lead Life MCF7 cell Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of prostate Malignant neoplasm of testis Mammalian Cell Mediating Mitochondria Molecular Morphology Mus Mutation Names Neuroblastoma Nuclear Oncogenic Organism PC3 cell line Pathway interactions Phosphatidylserines Physical condensation Play Process Radiation therapy Recovery Recurrence Research Role Shapes Skin Cancer Stimulus Structure System Therapeutic Time Tissues Transgenic Mice Treatment Failure United States National Institutes of Health Work base cancer cell cancer recurrence cancer therapy cancer type cell injury cell suicide cell type chemotherapy cytochrome c experience falls fly in vivo insight live cell imaging lung small cell carcinoma malignant breast neoplasm new therapeutic target novel public health relevance response screening small hairpin RNA small molecule tool treatment strategy tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy and radiotherapy kill cancer cells by inducing various types of cell death including apoptosis (Greek for "falling to death"), which is a natural cell suicide process. Primary cancers often exhibit dramatic initial responses to such therapies. However, most metastatic cancers, such as lung and pancreatic cancers, inevitably recur, leading to treatment failure. Apoptosis is generally assumed to be an intrinsically irreversible process. However we recently discovered an unexpected natural reversibility of execution-stage apoptosis in variety of human cancer cells and mouse primary cells. Dying cells can reverse apoptosis even after caspase-3 activation, which is widely believed to be the point of no return. We named this new recovery process anastasis (Greek for "rising to life"). Simply removing the apoptosis inducer can allow dying cells to reverse apoptosis, indicating that anastasis is a natural cellular recovery process. Notably, some cells that reverse apoptosis and harbor DNA damage appear to be transformed based on colony formation assays, and they have a higher frequency of chromosome rearrangements, suggesting that anastasis may promote survival of cells with oncogenic potential. Our findings lead to fundamental key questions: can reversal of apoptosis occur in vivo after treatment with apoptosis-inducing cancer therapies, and if so, can anastasis contribute in cancer recurrence after the therapies? In case true, anastasis would be a novel therapeutic target in cancer treatment. Recently, we have successfully developed a highly sensitive in vivo biosensor that allows us to identify cells that have undergone anastasis in Drosophila melanogaster. In Aim 1, we will develop new mammalian versions of the biosensor, and generate transgenic mice for future use to detect anastasis in vivo. In Aim 2, we propose to identify key regulators of anastasis. The proposed work has potential to uncover novel mechanisms of tumor development and evasion, and to provide new insights into the treatment of cancers by targeting anastasis.

描述（由申请人提供）：化疗和放疗通过诱导各种类型的细胞死亡（包括细胞凋亡（希腊语为“摔死”））来杀死癌细胞，这是一种治疗癌症的方法。自然细胞自杀过程原发性癌症通常对此类疗法表现出显著的初始反应。然而，大多数转移性癌症，如肺癌和胰腺癌，不可避免地复发，导致治疗失败。细胞凋亡通常被认为是一个本质上不可逆的过程。然而，我们最近在各种人类癌细胞和小鼠原代细胞中发现了一种意想不到的执行阶段凋亡的自然可逆性。即使在caspase-3激活后，死亡的细胞也可以逆转凋亡，这被广泛认为是不可逆的。我们将这种新的恢复过程命名为anastasis（希腊语，意为“复活”）。简单地去除凋亡诱导剂可以使垂死的细胞逆转凋亡，这表明愈合是一种自然的细胞恢复过程。值得注意的是，一些逆转凋亡和携带DNA损伤的细胞似乎是基于集落形成试验转化的，并且它们具有更高的染色体重排频率，这表明回缩可能促进具有致癌潜力的细胞的存活。我们的研究结果导致基本的关键问题：细胞凋亡的逆转是否会在体内发生，如果是的话，在治疗后的癌症复发的anastasis贡献？如果是真的，anastasis将成为癌症治疗的新靶点。最近，我们已经成功地开发了一种高灵敏度的体内生物传感器，使我们能够识别在果蝇经历了anastasis细胞。在目标1中，我们将开发新的哺乳动物版本的生物传感器，并产生转基因小鼠，用于未来检测体内anastasis。在目标2中，我们提出确定anastasis的关键调控因子。这项工作有可能揭示肿瘤发展和逃避的新机制，并为通过靶向anastasis治疗癌症提供新的见解。