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（应用程序提供）：化学疗法和放射疗法通过诱导各种类型的细胞死亡杀死癌细胞，包括凋亡（希腊语“跌至死亡”），这是自然细胞自杀过程。初级癌症经常暴露于此类疗法的戏剧性初始反应。但是，大多数转移性癌症，例如肺和胰腺癌，不可避免地会导致治疗失败。通常认为凋亡是本质上不可逆的过程。但是，我们最近发现了多种人类癌细胞和小鼠原代细胞中执行阶段凋亡的意外自然可逆性。即使在caspase-3激活后，垂死的细胞也会逆转凋亡，这被普遍认为是无回报的点。我们命名了这个新的恢复过程Anastasis（希腊语“崛起”）。简单地去除诱导的凋亡可以使垂死的细胞逆转凋亡，这表明anastasis是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损伤的细胞似乎是根据菌落形成测定而转化的，并且它们的染色体重排频率更高，这表明anastasis可能会促进具有致癌潜力的细胞的存活。我们的发现导致了基本的关键问题：用细胞凋亡诱导的癌症疗法治疗后的体内凋亡会发生逆转，如果是这样，阿纳斯塔症可以在疗法后会导致癌症复发吗？如果是的，则阿纳斯塔症将是癌症治疗中的新型治疗靶点。最近，我们成功地开发了一种高度敏感的体内生物传感器，使我们能够鉴定出在果蝇中经历过吻合的细胞。在AIM 1中，我们将开发新的哺乳动物版本的生物传感器，并生成转基因小鼠，以供将来使用以检测体内的anastasis。在AIM 2中，我们建议识别Anastasis的关键调节剂。拟议的工作有可能发现肿瘤发育和进化的新机制，并通过靶向吻合来提供有关癌症治疗的新见解。