Fas protects cancer stem cells from death

Fas 保护癌症干细胞免于死亡

• 批准号: 8891918
• 负责人: Marcus E. Peter
• 金额: $ 35.34万
• 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: 2015-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891918
• 关键词: Affect; Apoptosis; Automobile Driving; Biochemical; CD95 Antigens; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; ChIP-seq; Coin; Data; Development; Drug resistance; Event; Frequencies; Goals; Growth; Homeostasis; Human; Immune; Immune system; In Vitro; Ligands; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; MicroRNAs; Modeling; Mus; Necrosis; Outcome; Patients; Phosphorylation; Population; Proteins; Refractory; Resistance; Role; STAT1 gene; Scheme; Signal Transduction; Solid; Staging; Stem cells; System; TNFRSF6 gene; TNFSF6 gene; Techniques; Testing; Tissues; Up-Regulation; Woman; Work; Xenograft procedure; advanced disease; base; cancer cell; cancer stem cell; cancer type; established cell line; genome-wide; improved; in vivo; killings; knock-down; malignant breast neoplasm; mouse model; neoplastic cell; novel; public health relevance; receptor; receptor function; research study; therapy resistant; trait; tumor; Affect; Apoptosis; Automobile Driving; Biochemical; CD95 Antigens; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; ChIP-seq; Coin; Data; Development; Drug resistance; Event; Frequencies; Goals; Growth; Homeostasis; Human; Immune; Immune system; In Vitro; Ligands; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; MicroRNAs; Modeling; Mus; Necrosis; Outcome; Patients; Phosphorylation; Population; Proteins; Refractory; Resistance; Role; STAT1 gene; Scheme; Signal Transduction; Solid; Staging; Stem cells; System; TNFRSF6 gene; TNFSF6 gene; Techniques; Testing; Tissues; Up-Regulation; Woman; Work; Xenograft procedure; advanced disease; base; cancer cell; cancer stem cell; cancer type; established cell line; genome-wide; improved; in vivo; killings; knock-down; malignant breast neoplasm; mouse model; neoplastic cell; novel; public health relevance; receptor; receptor function; research study; therapy resistant; trait; tumor

 DESCRIPTION (provided by applicant): Cancer stem cells (CSCs, also called tumor initiating cells) are a rare population of cells present in many tumors. CSCs have the capacity to asymmetrically divide giving rise to nonstem cancer cells (nonCSCs) and more CSCs. CSCs are more resistant to therapy than nonCSCs, and a general observation is that therapy increases the number of CSCs. This likely contributes to the treatment resistance seen in patients with advanced disease. Great effort, therefore, is being placed at targeting CSCs in different cancers. Fas is a death receptor that can induce apoptosis in many tissues, most notably in the cells of the immune system. While Fas can kill tumor cells by inducing apoptosis under certain circumstances, we recently found that knocking down Fas or FasL induces a different form of cell death, necrosis, in all cancer cells. We coined this form of cell death DICE (for death induced by CD95/CD95L elimination). Preliminary data indicate that DICE preferentially affects CSCs suggesting that CSCs are addicted to Fas. Based on the observation that treatment refractory cancer is often enriched in CSCs induction of DICE creates an opportunity to target drug resistant cancers by eliminating CSCs. We hypothesize that Fas acts as an essential survival factor for CSCs and that DICE preferentially targets CSCs. We propose to study three specific aims: Specific Aim 1: Study the role of nonapoptotic Fas signaling, canonical Fas-mediated apoptosis, and DICE induction for CSCs and nonCSCs. Hypothesis: Fas can kill nonstem cancer cells (nonCSCs) but it is essential for the survival of CSCs. Specific Aim 2: Explore the mechanism of how Fas regulates CSC fate. Hypothesis: Fas mediates its CSC promoting activities through activation of STAT1. Specific Aim 3: Determine the effect of DICE induction on human CSCs in vivo. Hypothesis: Fas protects CSCs in primary cancers from death. This proposal will test the function of Fas as a protector of CSCs in breast and ovarian cancer. However, our data on multiple other cancer types (both cell lines and mouse models) suggest that this activity is not limited to women's cancer and may have fundamental significance for all solid cancers. This study will determine whether it is possible to deplete cancers of CSCs by inducing DICE and will begin the exploration of the downstream events that mediate this novel CSC-preserving activity of Fas. This proposal brings together recent findings on the role of Fas in cancer cells, the plasticity of CSCs, the function of miRNAs in CSCs, the role of CSCs in therapy resistance, and the concept of targeting CSCs with the ultimate goal to improve therapy.

 描述（由应用提供）：癌症干细胞（CSC，也称为肿瘤启动细胞）是许多肿瘤中存在的罕见细胞群。 CSC具有不对称分裂的能力，从而导致非茎癌细胞（NONCSC）和更多的CSC。与NONCSC相比，CSC对治疗更具耐药性，并且一般观察结果是治疗增加了CSC的数量。这可能有助于患有晚期疾病患者的治疗耐药性。因此，付出了巨大的努力，正在针对不同癌症的CSC进行付出。 FAS是一种死亡受体，可以多次诱导凋亡，最著名的是在免疫系统的细胞中。尽管在某些情况下，FAS可以通过诱导的凋亡杀死肿瘤细胞，但我们最近发现，在所有癌细胞中，击倒FAS或FASL会诱导不同形式的细胞死亡，坏死。我们创造了这种形式的细胞死亡骰子 （用于CD95/CD95L消除引起的死亡）。初步数据表明，骰子优先影响CSC，表明CSC被添加到FAS中。基于这样的观察，即治疗癌症通常富含CSC诱导的骰子诱导，从而通过消除CSC来靶向抗药性癌症。我们假设FA是CSC的基本生存因子，并且骰子优先针对CSC。我们建议研究三个具体目标：具体目标1：研究非凋亡FAS信号传导，规范FAS介导的凋亡以及CSC和NonCSC的骰子诱导的作用。假设：FA可以杀死非茎癌细胞（NONCSC），但对于CSC的存活至关重要。特定目标2：探索FAS如何调节CSC命运的机制。假设：FAS通过激活STAT1介导其CSC促进活动。特定目标3：确定骰子诱导对体内人类CSC的影响。假设：FAS保护原发性癌症中的CSC免受死亡。该提案将测试FAS作为CSC在乳腺癌和卵巢癌中的保护因子的功能。但是，我们关于其他多种癌症类型（细胞系和小鼠模型）的数据表明，这种活动不限于女性癌症，并且可能对所有固体癌症具有根本的意义。这项研究将确定是否有可能通过诱导骰子来减去CSC的癌症，并开始探索介导这种新型CSC的FAS活性的下游事件。该提案汇集了有关FAS在癌细胞中的作用，CSC的可塑性，miRNA在CSC中的功能，CSC在治疗耐药性中的作用以及针对CSC靶向CSC以改善治疗的最终目标的概念。