Fas protects cancer stem cells from death

 描述(申请人提供)：癌症干细胞(CSCs，也称为肿瘤起始细胞)是存在于许多肿瘤中的一种罕见的细胞群。CSCs具有不对称分裂的能力，产生非干细胞癌细胞(Non CSCs)和更多的CSCs。CSCs比非CSCs对治疗的抵抗力更强，一般的观察是治疗增加了CSCs的数量。这可能是晚期疾病患者出现治疗耐药性的原因之一。因此，人们正致力于针对不同癌症中的CSCs。Fas是一种死亡受体，可以在许多组织中诱导细胞凋亡，尤其是在免疫系统的细胞中。虽然在某些情况下，Fas可以通过诱导细胞凋亡来杀死肿瘤细胞，但我们最近发现，在所有的癌细胞中，敲除Fas或FasL会导致不同形式的细胞死亡，即坏死。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，DICE优先影响CSCs，提示CSCs对Fas上瘾。根据治疗难治性癌症通常富含CSCs的观察，DICE的诱导创造了通过消除CSCs来靶向耐药癌症的机会。我们假设Fas是CSCs的重要生存因子，DICE优先靶向CSCs。我们建议研究三个特定目标：特定目标1：研究非凋亡性Fas信号、规范的Fas介导的细胞凋亡和DICE诱导对CSCs和非CSCs的作用。假设：Fas可以杀死非干细胞癌细胞，但它对肿瘤干细胞的生存是必不可少的。具体目的2：探讨Fas调控CSC命运的机制。假设：Fas通过激活STAT1介导其对CSC的促进作用。具体目的3：确定骰子诱导对人体内CSCs的影响。假设：Fas保护原发癌患者的CSCs免于死亡。这项提议将测试Fas在乳腺癌和卵巢癌中作为CSCs保护者的功能。然而，我们在多种其他癌症类型(细胞系和小鼠模型)上的数据表明，这种活动不仅限于女性癌症，而且可能对所有实体癌症具有基本意义。这项研究将确定是否有可能通过诱导骰子来耗尽肿瘤干细胞，并将开始探索介导Fas这种新的肿瘤干细胞保护活性的下游事件。这一建议综合了关于Fas在癌细胞中的作用、CSCs的可塑性、CSCs中miRNAs的功能、CSCs在治疗抵抗中的作用以及以CSCs为靶点以提高治疗的最终目标的最新发现。

 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.