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

 描述(申请人提供)：我的实验室为我们理解死亡受体CD95(Fas)如何介导细胞凋亡做出了开创性的贡献。我们对CD95死亡诱导信号复合体(DISC)的发现影响了许多其他受体，并为包括TRAIL和肿瘤坏死因子受体在内的所有死亡受体的研究奠定了基础。我们发现了caspase-8，从而阐明了外在的细胞凋亡途径，这对癌症研究和其他领域都有意义。2004年，我的兴趣开始转向通过CD95传递非凋亡性信号。我们认识到CD95在几乎所有的细胞上都有表达，包括不应该发生凋亡的细胞(如神经元)，并且在几乎所有的癌细胞上都有表达，其中许多癌细胞在体外对CD95诱导的细胞凋亡高度敏感。2010年，这些研究突破性地发现，CD95通常会促进癌细胞的生长。在很大程度上基于这项工作，CD95L抑制剂已成功地用于临床试验。最近，我们报道了从癌细胞中消除CD95或CD95L会导致一种我称之为DICE(CD95R/L消除引起的死亡)的细胞死亡形式。引人注目的是，我们发现在所有被测试的癌细胞中(体外和体内)都可以诱导DICE，但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产生抗药性。这些数据表明，CD95起到了“死人开关”的作用，它通过多条信号通路确保低水平的生存信号，当它被移除时，多条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CD95刺激癌细胞或降低miR-200C水平会增加肿瘤干细胞(CSCs)的数量，CSCs对DICE的诱导比非CSCs更敏感，但对CD95介导的细胞凋亡不那么敏感。相反，诱导骰子或过表达miR-200C会减少CSCs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。DICE给我的印象是一种极其重要的癌症监测机制，我决定将这一提议的重点放在DICE及其机制、相关机制以及一种新的癌症治疗形式的开发上。我计划在接下来的7年里执行8个项目，没有特别的顺序，以8个问题的形式提出：1.从CD95发出的维持癌细胞存活的信号是什么？2.什么是调节CD95促进和维持CSCs活动的信号？3.什么细胞死亡途径包括DICE？4.是什么决定了正常细胞和癌细胞对DICE的敏感性的差异？5.免疫系统在DICE中的作用是什么？6.诱导DICE能否发展成一种新的癌症治疗形式？7.治疗耐药的癌症对DICE敏感吗？8.是否有其他肿瘤抑制因子可以作为靶点？我相信DICE和相关机制可以为癌症治疗提供一种新的方法，我深深地致力于将这种新的治疗方法带到临床上。

 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.