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（由适用提供）：我的实验室对我们对死亡受体CD95（FAS）如何介导凋亡的理解做出了第二种贡献。我们发现CD95死亡引起的信号传导复合物（DISC）影响了许多其他人，并为研究所有死亡受体（包括TRAIL和TNF受体）的研究奠定了基础。我们对caspase-8的发现导致阐明了外部凋亡途径，该途径对癌症研究及其他地区具有影响。 2004年，我的兴趣开始转向通过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，包括永远不应经历凋亡的细胞（例如神经元），并且在几乎所有癌细胞上都表达，其中许多细胞对通过体外CD95诱导的凋亡诱导高度敏感。在2010年，这些研究导致突破性发现CD95通常促进癌细胞的生长。基于这项工作，CD95L抑制剂已成功用于临床试验。最近，我们报道了癌细胞中CD95或CD95L的演变导致我称为骰子的细胞死亡形式（CD95R/L消除诱导的死亡）。令人惊讶的是，我们发现在所有经过测试的癌细胞（体外和体内）中都可以诱导骰子，并且还没有找到阻止它的方法，这表明癌细胞可能很难发展出对骰子的耐药性。数据表明，CD95充当“死人的开关”，可确保通过多个信号通路的低水平存活信号传导，并且当将其删除时，多个细胞死亡途径被激活。在2008年，我们发现MiR-200是EMT的关键调节剂。最近，我们发现CD95在癌细胞上的模拟或降低miR-200C水平会增加癌症干细胞的数量（CSC），这比非CSC对骰子的诱导更敏感，但对CD95介导的细胞凋亡的敏感性较小。相反，miR-200c的骰子或过表达的诱导减少了CSC的数量。我提出，骰子是通过消除损失CD95或CD95L的细胞来控制肿瘤转化过程中进化过程中产生的基本机制。骰子使我成为一种非常重要的癌症监测机制，我决定将此提案重点放在骰子上，其机制，相关机制以及一种新型癌症治疗形式的发展。我计划在未来7年中以8个问题的形式从事的未来7年进行8个项目。 2。介导促进和维护CSC的CD95活动的信号是什么？ 3。哪种细胞死亡途径包括骰子？ 4.是什么决定了正常和癌细胞之间对骰子骰子的敏感性差异？ 5。免疫系统在骰子中的作用是什么？ 6。是否可以将骰子诱导成为一种新型的癌症治疗形式？ 7。耐药性癌症是否容易受到骰子的影响？ 8。还有其他可以针对的肿瘤补充剂吗？我认为，骰子和相关机制可以提供一种新的癌症治疗方法，并且我非常致力于将这种新疗法带到诊所。