Targeting S1PR1/JAK2/STAT3 Signaling Axis in EMDR

该项目旨在确定有效的靶点，以解决癌症治疗面临的一个主要问题：骨 骨髓环境介导的耐药（EMDR）。一个潜在的关键目标，可以防止/减少 EMDR是STATS，部分原因是它在肿瘤细胞和肿瘤中持续激活 因为它是一种转录因子，调节许多促肿瘤微环境的表达， 和耐药因子。这些因素中的许多也是STATS激活剂，从而形成 feed-foHA/ard环连接肿瘤细胞与肿瘤微环境。IL-6，由骨髓基质细胞产生 细胞已被证明可以激活神经母细胞瘤细胞中的STATS（与项目1合作），导致 肿瘤生长和EMDR，我们的初步研究表明，在骨髓来源的细胞中， 防止肺内转移性肿瘤细胞的形成。然而，由于缺乏内在的 酶活性，没有临床试剂特异性靶向一些关键的致癌转录 如统计。我们最近的研究表明，STATS上调S1 PR 1的表达，这是一个关键因素。 磷脂代谢物G蛋白偶联受体。SI PRI反过来通过以下方式激活STATS： 酪氨酸激酶JAK 2，其也是IL-6受体信号传导的关键。在以下任一种中升高SI PRI表达： 肿瘤细胞或骨髓来源的骨髓细胞导致产生许多促进 STATs依赖的小生境形成为肿瘤细胞提供庇护所。此外，最近的研究表明， SIPRI介导实体和血源性癌症（包括ALL）的耐药性。重要的是，两者 SIPRI和JAK 2抑制剂最近进入临床试验。因此，我们建议测试假设 靶向骨髓基质细胞中的S1 PR 1/JAK 2/STAT 3信号通路将有效抑制EMDR， 神经母细胞瘤和急性淋巴细胞白血病我们将在神经母细胞瘤和ALL的共培养中检验我们的假设。 肿瘤细胞与小鼠和患者骨髓基质细胞，以及在同基因转基因小鼠和 异种移植神经母细胞瘤/ALL模型。我们还将采用一种新的体内异位骨形成系统， 复制肿瘤/骨髓小生境（小鼠和人）。随着转基因小鼠的出现， SiRNA技术允许在特定类型的骨髓中敲除/敲低S1 PR 1、JAK 2或STAT 3 细胞以及目前正在临床测试的小分子药物的可用性，我们提出的研究 可能导致范式转变的新疗法，以克服神经母细胞瘤，ALL和其他类型的EMDR， 癌

This project is aimed at identifying effective targets to address a major problem facing cancer treatment: bone marrow environment-mediated drug resistance (EMDR). One potential key target that may prevent/reduce EMDR is STATS, in part because it is persistenfiy activated in both tumor cells and in the tumor microenvironment, and because it is a transcription factor that regulates expression of numerous tumorpromoting and drug resistance factors. Many of these factors are also STATS activators, thereby forming a feed-foHA/ard loop linking tumor cells with the tumor microenvironment. lL-6, produced by bone marrow stromal cells has been shown to activate STATS in neuroblastoma cells (collaborative work with Project 1), leading to tumor growth and EMDR, Our preliminary studies show that ablafing STATS in bone marrow-derived cells prevents formation of lung niches that harbor metastatic tumor cells. However, due to a lack of intrinsic enzymatic activity, there are no clinical reagents to specifically target some of the key oncogenic transcription factors such as STATS. Our recent studies demonstrate that STATS upregulates expression of S1PR1, a key G protein-coupled receptor for the phospholipid metabolite, SIP. SI PRI, in turn, activates STATS through tyrosine kinase JAK2, which is also critical for IL-6 receptor signaling. Elevafing SI PRI expression in either tumor cells or bone marrow-derived myeloid cells leads to production of numerous factors that promote STATS-dependent niche formation to provide sanctuary for tumor cells. Furthermore, recent studies implicate SI PRI in mediating drug resistance of both solid and blood-borne cancers, including ALL. Importantly, both SI PRI and JAK2 inhibitors have recently entered clinical trials. We therefore propose to test the hypothesis that targeting S1PR1/JAK2/STAT3 signaling in bone marrow stromal cells will effectively inhibit EMDR for both neuroblastoma and ALL. We will test our hypothesis in co-cultures of neuroblastoma and ALL tumor cells with mouse and patient bone marrow stromal cells, and in syngeneic transgenic mouse and xenograft neuroblastoma/ALL models. We will also adapt a novel in vivo ectopic bone-forming system to reproduce the tumor/bone marrow niche (both mouse and human). With the availability of transgenic mice and SiRNA technologies allowing S1PR1, JAK2, or STAT3 knockout/knockdown in specific types of bone marrow cells as well as the availability of small molecule drugs currently under clinical tesfing, our proposed studies may lead to paradigm-shifting novel therapies to overcome EMDR in neuroblastoma, ALL, and other types of cancer.