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: 9313238
• 负责人: Marcus E. Peter
• 金额: $ 91.4万
• 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/9313238
• 关键词: Apoptosis; CASP8 gene; Cancer Cell Growth; Cell Death; Cells; Cessation of life; Clinic; Clinical Trials; Complex; Data; Development; Employee Strikes; 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）：我的实验室对我们理解死亡受体CD 95（Fas）如何介导细胞凋亡做出了开创性贡献。我们对CD 95死亡诱导信号复合物（DISC）的发现影响了许多其他人，并为所有死亡受体（包括TRAIL和TNF受体）的研究奠定了基础。我们发现的胱天蛋白酶-8导致阐明的外源性凋亡途径，这对癌症研究和超越的影响。2004年，我的兴趣开始转向通过CD 95的非凋亡信号。我们认识到，CD 95在几乎所有细胞上表达，包括不应该经历凋亡的细胞（例如，神经元），并且几乎在所有癌细胞上表达，其中许多在体外对通过CD 95的凋亡诱导高度敏感。2010年，这些研究导致了突破性的发现，即CD 95通常促进癌细胞的生长。在很大程度上基于这项工作，CD 95 L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CD 95或CD 95 L会导致一种细胞死亡形式，我称之为DICE（CD 95 R/L消除诱导的死亡）。引人注目的是，我们发现DICE可以在所有测试的癌细胞中诱导（体外和体内），我们还没有找到阻断它的方法，这表明癌细胞可能很难对DICE产生耐药性。数据表明，CD 95作为一个“死亡开关”，通过多种信号传导途径确保低水平的存活信号，当它被去除时，多个细胞死亡途径被激活。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CD 95或降低miR-200 c水平增加了癌症干细胞（CSC）的数量，这些细胞对DICE的诱导比非CSC更敏感，但对CD 95介导的凋亡不太敏感。相反，诱导DICE或过表达miR-200 c会减少CSC的数量。我提出DICE是在进化过程中产生的一种基本机制，通过消除失去CD 95或CD 95 L的细胞来控制肿瘤转化。DICE作为一种非常重要的癌症监测机制给我留下了深刻的印象，我决定将这个建议集中在DICE，它的机制，相关机制以及一种新的癌症治疗形式的发展上。我计划在未来7年内开展8个项目，不分先后，以8个问题的形式呈现在这里：1。从CD 95发出的信号是什么，使癌细胞存活？2.哪些信号介导CD 95促进和维持CSC的活性？3. DICE包含哪些细胞死亡途径？4.是什么决定了正常细胞和癌细胞对DICE敏感性的差异？5.免疫系统在DICE中的作用是什么？6. DICE的诱导能发展成一种新的癌症治疗形式吗？7.耐药癌症对DICE敏感吗？8.还有其他的肿瘤抑制剂可以靶向吗？我相信DICE和相关机制可以为癌症治疗提供一种新的方法，我非常致力于将这种新的治疗方法引入临床。