Elucidating connections between anastasis and cancer drug resistance

项目摘要 激活程序性细胞死亡如凋亡是最重要的治疗策略之一 用于癌症治疗。许多癌症对这种疗法的最初反应是戏剧性的。然而，癌症 随着耐药性的发展而复发是大多数 癌症，导致治疗失败。细胞死亡的经典观点一直认为， 一旦启动，凋亡死亡过程是不可逆的。然而，我们发现垂死的癌症 细胞和原代细胞甚至在晚期执行阶段也可以逆转凋亡过程，并将其命名为 细胞恢复机制Anastasis（希腊语为“上升到生命”）。anastasis的发现表明 这是一种意想不到的策略，癌细胞可以用来逃避诱导细胞死亡的癌症治疗。的核心 根据这一提议，我们已经证明，一些细胞在发育过程中获得了永久性的遗传变化。 anastasis和经历致癌转化的频率高于对照组。此外，委员会认为， 促分化细胞显示出对细胞凋亡刺激物如抗癌药物的抗性增加。这些 这些观察引出了一个有趣的问题：anastasis是否有助于药物的开发？ 复发性肿瘤的耐药性？如果是这样的话，anastasis将是一个潜在的和新的治疗靶点， 抑制癌症进展和复发。由于突变有助于 耐药性，我们提出，癌细胞存活的anastasis发生在周期之间的间隔， 抗癌治疗可能会使乳腺癌引起的DNA损伤永久化， 突变、进展和复发性癌症中耐药性的演变。在具体目标1中， 我建议测试和鉴定这些突变，如果它们发生，并确定突变热点是否 存在于细胞中。然后，我们将比较任何确定的突变与已知的突变 在复发性临床肿瘤中绘制的签名。这将直接测试连接 在癌细胞中连接和突变之间的联系。在具体目标2中，我们建议比较 促分化癌细胞对不同细胞死亡诱导物的敏感性。已经恢复的消化细胞 来自细胞凋亡的重复诱导的细胞通常对相同的细胞死亡刺激产生抗性。然而，在这方面， 尚不清楚这些再分化细胞是否也对其它细胞死亡诱导剂具有抗性。我们将 通过确定anastasis是否增加癌细胞对更高水平的抵抗力来测试这种可能性。 剂量的相同诱导剂，并且还可能导致对其他细胞死亡途径的"交叉抗性"，例如， 自噬、铁凋亡和坏死性凋亡。总的来说，这些研究试图阐明 癌细胞的耐药性的恢复和发展，可以靶向和用于新的 抗癌治疗的方法。

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.