DISE - a natural cancer surveillance mechanism - a new road to cancer therapy

DISE——天然癌症监测机制——癌症治疗新之路

• 批准号: 9753713
• 负责人: Marcus E. Peter
• 金额: $ 88.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753713
• 关键词: Apoptosis; CASP8 gene; Cancer Cell Growth; Cell Death; Cells; Cessation of life; Clinic; Clinical Trials; Complex; Data; Development; Ensure; Evolution; Immune system; In Vitro; Induction of Apoptosis; Malignant Neoplasms; Mediating; Neoplastic Cell Transformation; Neurons; Normal Cell; Pathway interactions; Reporting; Resistance development; Role; Seminal; Signal Pathway; Signal Transduction; TNFRSF6 gene; TNFSF10 gene; TNFSF6 gene; Testing; Time; Tumor Necrosis Factor Receptor; Tumor Suppressor Proteins; Work; anticancer research; base; cancer cell; cancer stem cell; cancer therapy; in vivo; inhibitor/antagonist; interest; man; novel; novel strategies; overexpression; public health relevance; receptor; therapy resistant; virtual

 DESCRIPTION (provided by applicant): My lab has made seminal contributions to our understanding of how the death receptor CD95 (Fas) mediates apoptosis. Our discovery of the CD95 death-inducing signaling complex (DISC) has influenced many others, and has laid the groundwork for the study of all death receptors, including TRAIL and TNF receptors. Our discovery of caspase-8 resulted in elucidation of the extrinsic apoptosis pathway, which has had implications for cancer research and beyond. In 2004, my interest began to turn toward nonapoptotic signaling through CD95. We recognized that CD95 was expressed on virtually all cells, including cells that should never undergo apoptosis (e.g., neurons), and was expressed on virtually all cancer cells, many of which were highly sensitive to apoptosis induction through CD95 in vitro. In 2010 these studies led to the break-through discovery that CD95 generally promotes growth of cancer cells. Based largely on this work, a CD95L inhibitor has been successfully used in clinical trials. More recently, we reported that elimination of CD95 or CD95L from cancer cells results in a form of cell death that I have termed DICE (death induced by CD95R/L elimination). Strikingly, we have found that DICE can be induced in all cancer cells tested (in vitro and in vivo), and we have not found a way to block it, suggesting that cancer cells may have a hard time developing resistance to DICE. The data suggest that CD95 acts as a "dead man's switch", which ensures low level survival signaling through multiple signaling pathways, and when it is removed multiple cell death pathways are activated. In 2008 we discovered that miR-200 is a key regulator of EMT. Most recently, we found that stimulation of CD95 on cancer cells or reducing miR-200c levels increases the number of cancer stem cells (CSCs), which are more sensitive to induction of DICE than non-CSCs but are less sensitive to CD95 mediated apoptosis. In contrast, induction of DICE or overexpression of miR-200c reduces the number of CSCs. I proposed that DICE is a fundamental mechanism arising during evolution to control neoplastic transformation by eliminating cells that have lost either CD95 or CD95L. DICE strikes me as being a profoundly important cancer surveillance mechanism, and I have decided to focus this proposal on DICE, its mechanisms, related mechanisms, and the development of a novel form of cancer therapy. I am planning to pursue 8 projects over the next 7 years presented here, in no particular order, in the form of 8 questions: 1. What are the signals emanating from CD95 that keep cancer cells alive? 2. What are the signals that mediate the activities of CD95 that promote and maintain CSCs? 3. What cell death pathways comprise DICE? 4. What determines the difference in sensitivity to DICE between normal and cancer cells? 5. What is the role of the immune system in DICE? 6. Can induction of DICE be developed into a novel form of cancer therapy? 7. Are therapy resistant cancers susceptible to DICE? 8. Are there other tumor suppressors that can be targeted? I believe that DICE and related mechanisms can provide a new approach to cancer therapy, and I am deeply committed to bringing this new treatment to the clinic.

 描述（由申请人提供）：我的实验室为我们了解死亡受体 CD95 (Fas) 如何介导细胞凋亡做出了开创性贡献。我们对 CD95 死亡诱导信号复合物 (DISC) 的发现影响了许多其他受体，并为所有死亡受体（包括 TRAIL 和 TNF 受体）的研究奠定了基础。我们对 caspase-8 的发现阐明了外源性细胞凋亡途径，这对癌症研究及其他领域具有重要意义。 2004 年，我的兴趣开始转向 CD95 的非凋亡信号传导。我们认识到，CD95几乎在所有细胞上表达，包括不应该发生凋亡的细胞（例如神经元），并且在几乎所有癌细胞上表达，其中许多癌细胞对体外CD95诱导的细胞凋亡高度敏感。 2010 年，这些研究取得了突破性发现：CD95 通常会促进癌细胞的生长。很大程度上基于这项工作，CD95L抑制剂已成功用于临床试验。最近，我们报道了从癌细胞中消除 CD95 或 CD95L 会导致一种细胞死亡形式，我将其称为 DICE（CD95R/L 消除诱导的死亡）。引人注目的是，我们发现所有测试的癌细胞（体外和体内）都可以诱导 DICE，而且我们还没有找到阻止它的方法，这表明癌细胞可能很难对 DICE 产生耐药性。数据表明，CD95充当“死人开关”，通过多种信号通路确保低水平的生存信号传导，当它被移除时，多种细胞死亡通路被激活。 2008年我们发现miR-200是EMT的关键调节因子。最近，我们发现刺激癌细胞上的 CD95 或降低 miR-200c 水平会增加癌症干细胞 (CSC) 的数量，这些细胞比非 CSC 对 DICE 的诱导更敏感，但对 CD95 介导的细胞凋亡不太敏感。相反，DICE 的诱导或 miR-200c 的过度表达会减少 CSC 的数量。我提出 DICE 是进化过程中产生的一种基本机制，通过消除丢失 CD95 或 CD95L 的细胞来控制肿瘤转化。我认为 DICE 是一种非常重要的癌症监测机制，我决定将这项提案的重点放在 DICE、其机制、相关机制以及新型癌症治疗的开发上。我计划在接下来的 7 年里开展 8 个项目，这些项目（排名不分先后）以 8 个问题的形式进行： 1. CD95 发出哪些信号可以保持癌细胞的存活？ 2. 介导 CD95 促进和维持 CSC 活动的信号是什么？ 3. DICE 包括哪些细胞死亡途径？ 4. 正常细胞和癌细胞对 DICE 敏感性的差异是由什么决定的？ 5. 免疫系统在DICE中起什么作用？ 6. DICE诱导能否发展成为一种新型的癌症治疗方法？ 7. 治疗耐药的癌症是否容易受到 DICE 的影响？ 8. 还有其他可以靶向的肿瘤抑制因子吗？我相信DICE和相关机制可以为癌症治疗提供一种新的方法，我坚定地致力于将这种新的治疗方法带到临床。