Understanding the role of autophagy-regulated cell death in the escape from replicative crisis

了解自噬调节的细胞死亡在逃避复制危机中的作用

• 批准号: 10063861
• 负责人: Jan Karlseder
• 金额: $ 63.88万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063861
• 关键词: Apoptosis; Apoptotic; Applications Grants; Autophagocytosis; Bypass; Cancerous; Cell Aging; Cell Cycle Checkpoint; Cell Death; Cell Nucleus; Cell Proliferation; Cells; DNA; DNA Damage; Data; Development; Event; Functional disorder; Genome; Genomic Instability; Genotoxic Stress; Goals; Growth; Human; Impairment; Individual; Lead; Learning; Malignant - descriptor; Malignant Neoplasms; Mitochondria; Molecular; Nature; Organelles; Organism; Pathway interactions; Phase; Population; Process; Proliferating; Proteins; Resistance; Ribosomes; Role; Signal Pathway; Signal Transduction; Site; Stimulator of Interferon Genes; Stress; TP53 gene; Telomere Maintenance; Testing; Time; Tumor Escape; Tumor Suppression; Tumor Suppressor Proteins; Up-Regulation; base; cancer cell; design; expectation; genome integrity; genome-wide; genomic aberrations; in vivo; inhibition of autophagy; inhibitor/antagonist; loss of function; mouse model; neoplastic; neoplastic cell; novel; peroxisome; prevent; response; senescence; telomere; tool; tumor; tumorigenesis

Abstract Tumor cells arise upon escape from two distinct and critical barriers that limit proliferation of human cells, replicative senescence and crisis. Cells in replicative senescence arrest permanently while continuing to metabolize, triggered by short telomeres. Senescence entry however, is avoided by impairment of the main cell cycle checkpoints controlled by the p53 and Rb tumor suppressive pathways. Following senescence bypass and continued proliferation, cells undergo crisis, which is a phase highlighted by substantial telomere deprotection and widespread cell death. Crisis is a stringent tumor-suppressive barrier, as it removes the vast majority of cells that avoid senescence. However, rarely cells overcome this barrier and become neoplastic. The molecular mechanisms and pathways underlying cell death in crisis and spontaneous crisis evasion are not understood. Here, it is proposed to investigate the molecular mechanisms underlying the escape from crisis and crisis bypass, with the expectation that the resulting discoveries will have a strong impact on our understanding of the early steps in cancer development. The preliminary data presented here suggest a novel concept for replicative crisis that implicates autophagy as a major regulator of cell death. Autophagy suppression allowed cells to bypass crisis and continue to proliferate, while accumulating multiple genomic aberrations. This discovery is of profound significance for understanding how genome instability evolves during the early steps of cancer development. Furthermore, the finding suggests that autophagy inhibitors might have counterproductive effects and promote the establishment of neoplastic cells instead of eliminating them. In three specific aims it is proposed to decipher the exact signaling pathways that lead from dysfunctional telomeres to the activation of autophagy-controlled cell death (Aim 1), to determine the consequences of telomere-driven autophagy and of autophagy inhibition during crisis (Aim 2), and to understand the role of autophagy-driven cell death in crisis on tumor development in vivo (Aim 3). In summary, this grant proposal focuses on the mechanisms underlying cell death during replicative crisis, the mechanism of how autophagy is activated and regulated in response to replicative crisis, and how inhibition of autophagy during crisis enables cells with an unstable genome to escape this final barrier against tumor cell establishment and drive malignancy. We will thereby explore our novel hypothesis, in which temporary or permanent resistance to autophagic cell death is the initial event required for the emergence of post-crisis cells and an abrupt rise in genome instability, leading to the establishment of neoplastic cells.

抽象的 肿瘤细胞在逃离限制人类细胞增殖的两个不同且关键的屏障时产生， 复制性衰老和危机。复制性衰老细胞永久停滞，同时继续 由短端粒触发的新陈代谢。然而，通过主细胞的损伤可以避免进入衰老 由 p53 和 Rb 肿瘤抑制途径控制的周期检查点。遵循衰老旁路和 持续增殖，细胞经历危机，这是一个以大量端粒脱保护为突出的阶段 和广泛的细胞死亡。危机是一个严格的肿瘤抑制屏障，因为它消除了绝大多数细胞 从而避免衰老。然而，很少有细胞能够克服这一屏障并变成肿瘤。分子 危机中细胞死亡和自发危机逃避的机制和途径尚不清楚。 在这里，建议研究逃避危机和危机绕行的分子机制， 期望由此产生的发现将对我们对早期的理解产生重大影响 癌症发展的步骤。这里提供的初步数据提出了复制危机的新概念 这表明自噬是细胞死亡的主要调节因子。自噬抑制允许细胞绕过 危机并继续增殖，同时积累多种基因组畸变。这个发现意义深远 对于理解癌症发展早期阶段基因组不稳定性如何演变具有重要意义。 此外，研究结果表明自噬抑制剂可能会产生适得其反的作用并促进 肿瘤细胞的建立而不是消除它们。在三个具体目标中，建议破译 导致从功能失调的端粒到自噬控制的激活的确切信号通路 细胞死亡（目标 1），以确定端粒驱动的自噬和自噬抑制的后果 危机期间（目标 2），并了解危机期间自噬驱动的细胞死亡对肿瘤发展的作用 体内（目标 3）。总之，这项拨款提案的重点是细胞死亡过程中的潜在机制。 复制危机，如何激活和调节自噬以应对复制危机的机制， 以及在危机期间抑制自噬如何使基因组不稳定的细胞逃脱这最后的障碍 对抗肿瘤细胞的建立并促进恶性肿瘤。因此，我们将探索我们的新假设，其中 对自噬细胞死亡的暂时或永久抵抗是出现所需的初始事件 危机后细胞和基因组不稳定性突然上升，导致肿瘤细胞的形成。