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来杀死癌细胞，包括细胞凋亡（希腊语“坠落死亡”），这是一种自然细胞自杀过程。然而，大多数转移性癌症，如肺癌和胰腺癌，不可避免地会复发，导致治疗失败。最近发现，在多种人类癌细胞和小鼠原代细胞中，死亡细胞即使在 caspase-3 激活后也能逆转细胞凋亡，这被广泛认为是“不归路”。这种新的恢复过程 anastasis（希腊语，意为“复活”）只需去除凋亡诱导剂就可以使垂死的细胞逆转细胞凋亡，这表明 anastasis 是一种自然的细胞恢复过程。值得注意的是，出现了一些逆转细胞凋亡并含有 DNA 损伤的细胞。根据集落形成测定进行转化，并且它们具有更高频率的染色体重排，这表明吻合可能促进具有致癌潜力的细胞的存活，我们的研究结果引出了基本的关键问题：治疗后体内细胞凋亡是否可以逆转。与诱导细胞凋亡的癌症疗法相比，如果是这样，那么吻合术是否会导致治疗后的癌症复发？如果属实的话，吻合术将成为癌症治疗中的一个新的治疗靶标。最近，我们成功开发了一种高度灵敏的体内生物传感器。我们将鉴定果蝇中经历过吻合的细胞。在目标 1 中，我们将开发新的哺乳动物版本的生物传感器，并生成转基因小鼠以供将来用于检测体内吻合。目标 2，我们建议确定吻合的关键调节因子，这项工作有可能揭示肿瘤发展和逃避的新机制，并为通过靶向吻合来治疗癌症提供新的见解。