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

基本信息

  • 批准号:
    10224839
  • 负责人:
  • 金额:
    $ 91.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CD95/Fas suppresses NF-κB activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism.
  • DOI:
    10.1016/j.isci.2021.103538
  • 发表时间:
    2021-12-17
  • 期刊:
  • 影响因子:
    5.8
  • 作者:
    Guégan JP;Pollet J;Ginestier C;Charafe-Jauffret E;Peter ME;Legembre P
  • 通讯作者:
    Legembre P
Death Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer's disease and aging.
  • DOI:
    10.1038/s41467-023-44465-8
  • 发表时间:
    2024-01-18
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Paudel, Bidur;Jeong, Si-Yeon;Martinez, Carolina Pena;Rickman, Alexis;Haluck-Kangas, Ashley;Bartom, Elizabeth T;Fredriksen, Kristina;Affaneh, Amira;Kessler, John A;Mazzulli, Joseph R;Murmann, Andrea E;Rogalski, Emily;Geula, Changiz;Ferreira, Adriana;Heckmann, Bradlee L;Green, Douglas R;Sadleir, Katherine R;Vassar, Robert;Peter, Marcus E
  • 通讯作者:
    Peter, Marcus E
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Marcus E. Peter其他文献

Expression of c-FLIP<sub>L</sub> and resistance to CD95-mediated apoptosis of monocyte-derived dendritic cells: inhibition by bisindolylmaleimide
  • DOI:
    10.1182/blood.v95.11.3478
  • 发表时间:
    2000-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Fabienne Willems;Zoulikha Amraoui;Nathalie Vanderheyde;Valérie Verhasselt;Ezra Aksoy;Carsten Scaffidi;Marcus E. Peter;Peter H. Krammer;Michel Goldman
  • 通讯作者:
    Michel Goldman
Mapping of Ras-related GTP-binding proteins by GTP overlay following two-dimensional gel electrophoresis.
二维凝胶电泳后通过 GTP 覆盖图绘制 Ras 相关 GTP 结合蛋白。
AIDS and the death receptors.
艾滋病和死亡受体。
  • DOI:
  • 发表时间:
    1997
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Marcus E. Peter;A. Ehret;Christina Berndt;P. H. Krammer
  • 通讯作者:
    P. H. Krammer
The two CD95 apoptosis signaling pathways may be a way of cells to respond to different amounts and/or forms of CD95 ligand produced in different tissues
这两条CD95凋亡信号通路可能是细胞对不同组织中产生的不同量和/或形式的CD95配体作出反应的一种方式
  • DOI:
    10.1038/sj.cdd.4400707
  • 发表时间:
    2000
  • 期刊:
  • 影响因子:
    12.4
  • 作者:
    Ingo Schmitz;Henning Walczak;P. H. Krammer;Marcus E. Peter
  • 通讯作者:
    Marcus E. Peter
APO‐1(CD95)‐mediated apoptosis in Jurkat cells does not involve src kinases or CD45
Jurkat 细胞中 APO-1(CD95) 介导的细胞凋亡不涉及 src 激酶或 CD45
  • DOI:
  • 发表时间:
    1995
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    B. Schraven;Marcus E. Peter
  • 通讯作者:
    Marcus E. Peter

Marcus E. Peter的其他文献

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{{ truncateString('Marcus E. Peter', 18)}}的其他基金

Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer
Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性
  • 批准号:
    10514907
  • 财政年份:
    2022
  • 资助金额:
    $ 91.4万
  • 项目类别:
Novel immune suppressive activities of Fas/CD95 in triple negative breast cancer
Fas/CD95 在三阴性乳腺癌中的新型免疫抑制活性
  • 批准号:
    10661817
  • 财政年份:
    2022
  • 资助金额:
    $ 91.4万
  • 项目类别:
6mer seed toxicity and AIDS
6mer 种子毒性和艾滋病
  • 批准号:
    10132980
  • 财政年份:
    2020
  • 资助金额:
    $ 91.4万
  • 项目类别:
Fas protects cancer stem cells from death
Fas 保护癌症干细胞免于死亡
  • 批准号:
    8891918
  • 财政年份:
    2015
  • 资助金额:
    $ 91.4万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 91.4万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 91.4万
  • 项目类别:
DICE - a natural cancer surveillance mechanism - a new road to cancer therapy
DICE——自然癌症监测机制——癌症治疗新之路
  • 批准号:
    9122387
  • 财政年份:
    2015
  • 资助金额:
    $ 91.4万
  • 项目类别:
The role of Fas as tumor promoter
Fas作为肿瘤促进剂的作用
  • 批准号:
    8187162
  • 财政年份:
    2005
  • 资助金额:
    $ 91.4万
  • 项目类别:
The role of Fas as tumor promoter
Fas作为肿瘤促进剂的作用
  • 批准号:
    8528496
  • 财政年份:
    2005
  • 资助金额:
    $ 91.4万
  • 项目类别:
The Role of CD95 as a Tumor Promoter
CD95 作为肿瘤启动子的作用
  • 批准号:
    7250259
  • 财政年份:
    2005
  • 资助金额:
    $ 91.4万
  • 项目类别:
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