Fas protects cancer stem cells from death

 描述（由申请人提供）：癌症干细胞（CSC，也称为肿瘤起始细胞）是存在于许多肿瘤中的罕见细胞群。CSC具有不对称分裂的能力，产生非干细胞癌细胞（nonCSC）和更多的CSC。CSC比非CSC对治疗更具抗性，并且一般观察结果是治疗增加了CSC的数量。这可能有助于在晚期疾病患者中观察到的治疗抗性。因此，人们正在努力靶向不同癌症中的CSC。Fas是一种死亡受体，可以诱导许多组织中的细胞凋亡，特别是在免疫系统的细胞中。虽然Fas在某些情况下可以通过诱导凋亡来杀死肿瘤细胞，但我们最近发现，在所有癌细胞中，敲低Fas或FasL会诱导不同形式的细胞死亡，即坏死。我们创造了这种细胞死亡骰子 (for由CD 95/CD 95 L消除诱导的死亡）。初步数据表明，DICE优先影响CSC，表明CSC对Fas成瘾。基于治疗难治性癌症通常富含CSC的观察结果，DICE的诱导创造了通过消除CSC靶向耐药癌症的机会。我们假设Fas是CSC的一个重要生存因子，DICE优先靶向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，经典Fas介导的凋亡，以及CSCs和nonCSCs的DICE诱导的作用。假设：Fas可以杀死非干细胞癌细胞（nonCSCs），但它对CSCs的存活至关重要。具体目标2：探讨Fas调控CSC命运的机制。假说：Fas通过激活STAT 1介导其对CSC的促进作用。具体目标3：确定DICE诱导对体内人CSC的影响。假设：Fas保护原发性癌症中的CSC免于死亡。该提案将测试Fas作为乳腺癌和卵巢癌中CSC的保护者的功能。然而，我们对多种其他癌症类型（细胞系和小鼠模型）的数据表明，这种活性不仅限于女性癌症，而且可能对所有实体癌都具有根本意义。本研究将确定是否有可能通过诱导DICE来消除癌症的CSC，并将开始探索介导Fas这种新的CSC保留活性的下游事件。该提案汇集了有关Fas在癌细胞中的作用、CSC的可塑性、CSC中miRNA的功能、CSC在治疗抗性中的作用以及靶向CSC的概念的最新发现，最终目标是改善治疗。

 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.