Cell survival by anastasis, a novel therapeutic target in cancer

 描述(申请人提供)：化疗和放射治疗通过诱导包括细胞凋亡在内的各种类型的细胞死亡来杀死癌细胞(希腊语中“坠落死亡”的意思)，这是一种 自然的细胞自杀过程。原发性癌症通常对这种疗法表现出戏剧性的初始反应。然而，大多数转移性癌症，如肺癌和胰腺癌，不可避免地会复发，导致治疗失败。细胞凋亡通常被认为是一个本质上不可逆转的过程。然而，我们最近在多种人类癌细胞和小鼠原代细胞中发现了一种出人意料的自然可逆性，即执行期细胞凋亡。死亡细胞即使在caspase-3激活后也可以逆转凋亡，而caspase-3被广泛认为是不归路的点。我们将这一新的恢复过程命名为Anastsis(希腊语中“复活”的意思)。简单地去除凋亡诱导剂就可以使濒死的细胞逆转凋亡，这表明再转移是一个自然的细胞恢复过程。值得注意的是，一些逆转细胞凋亡和隐藏DNA损伤的细胞似乎在克隆形成分析的基础上发生了转化，它们有更高的染色体重排频率，这表明转移可能促进具有致癌潜力的细胞的存活。我们的发现引出了一些基本的关键问题：在用诱导细胞凋亡的癌症疗法治疗后，细胞凋亡能否在体内发生逆转？如果是的话，肿瘤转移是否会在治疗后导致癌症复发？如果情况属实，Anastasis将成为癌症治疗的新治疗靶点。最近，我们成功地开发了一种高灵敏的在体生物传感器，使我们能够识别经历了黑腹果蝇转移的细胞。在目标1中，我们将开发新的哺乳动物版本的生物传感器，并产生转基因小鼠，以便将来用于检测体内的转移。在目标2中，我们建议确定Anastasis的关键调控因子。这项拟议的工作有可能揭示肿瘤发展和逃避的新机制，并通过靶向转移为癌症的治疗提供新的见解。

 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.