Elucidating connections between anastasis and cancer drug resistance

项目摘要 激活程序性细胞死亡，如细胞凋亡，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 复发与耐药性的发展是大多数临床治疗中的主要问题。 癌症类型，导致治疗失败。细胞死亡的经典观点长期以来一直假设， 一旦启动，凋亡死亡过程是不可逆转的。然而，我们发现濒临死亡的癌症 即使在执行后期，细胞和原代细胞也可以逆转凋亡过程，并将其命名为 细胞恢复机制阿纳斯塔西(希腊语“复活”的意思)。阿纳斯塔西斯的发现表明 癌细胞可以用来逃避细胞死亡诱导癌症治疗的意想不到的策略。中心到 这一建议，我们已经证明了一些细胞获得了永久性的遗传变化 肿瘤转移和发生致癌转化的频率高于对照组。此外， 再生细胞对抗癌药物等凋亡刺激的抵抗力增强。这些 观察结果引出了一个耐人寻味的问题：阿纳斯塔西能对药物的开发做出贡献吗？ 复发肿瘤的耐药性？如果是这样的话，Anastsis将是一个潜在的和新的治疗靶点 抑制癌症进展和复发。因为突变有助于人类的发展 耐药性，我们认为癌细胞通过转移存活发生在周期之间的间隔 抗癌治疗可以使细胞凋亡引起的DNA损伤持续存在，并导致 复发癌症中耐药的突变、进展和进化。在具体目标1中，我们 建议检测和识别此类突变，如果它们发生，并确定突变热点 存在于无核细胞中。然后我们将比较任何与已知突变相匹配的突变 在复发的临床肿瘤中已被映射的特征。这将直接测试连接 癌细胞的转移和突变之间的关系。在具体目标2中，我们建议将 肿瘤细胞对不同细胞死亡诱导剂的敏感性。已恢复的再生细胞 由于反复诱导细胞凋亡，往往对相同的细胞死亡刺激产生抵抗力。然而， 目前尚不清楚这些再生细胞是否对其他细胞死亡诱导剂也有抵抗力。我们会 通过确定转移是否增加癌细胞对更高水平的耐药性来测试这种可能性 同样剂量的诱导剂，也可能导致对其他细胞死亡途径的“交叉耐药”，例如， 自噬、铁性下垂和坏死性下垂。总体而言，这些研究试图阐明 肿瘤细胞的转移和耐药性的发展，可作为新的靶向和有用的 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.