Defining extracellular vesicle-mediated drug resistance in AML

项目摘要 急性髓系白血病(AML)是一种侵袭性、遗传异质性的癌症，影响两者 儿童和成人--由骨髓(BM)中的异常髓系细胞引起。虽然很多病人 在诱导化疗后获得缓解，由于复发，5年存活率仍然是令人沮丧的25% 对抗癌药物的抗药性越来越强。AML重塑了BM微环境，部分是通过发布 膜结合的胞外小泡(EVS)，调节受体细胞。我们发现电动汽车转移 内质网-应激至基质细胞，导致特定细胞类型的表型变化，从而改变 BM的细胞组成。有趣的是，这些EV还被发现含有骨形态发生蛋白。 (BMP)--强大的生长因子与耐药性和癌症进展有关。目前对此知之甚少 关于EV介导的内质网应激和BMPs的传递如何有助于形成化学保护性利基。 多项研究表明，内质网应激可以在肿瘤微环境中的细胞之间传递， 在实体肿瘤模型中导致耐药性。在AML的背景下，我们发现电动汽车本身就是 足以传递内质网应激并激活受体基质中的未折叠蛋白反应(UPR)途径 细胞。在体内，由于肿瘤微环境中的生理应激，AML细胞表现出明显的UPR。我们有 研究发现，UPR途径的上调与UPR的表达和包装增加相一致 电动汽车上有多种BMP类型。因为UPR和BMP之前都被认为与促进癌症有关 生存和耐药性，我们建议研究EVS在将适应性变化传递给接受者中的作用 BM细胞形成化学保护环境。此外，由于越来越多的证据表明，AML-EVS 重塑骨髓微环境，阻断EV的生物发生已成为AML明显的治疗靶点。 我们假设EV介导的未折叠蛋白反应和骨形态发生的传递 蛋白质促进AML耐药的适应性变化，这种变化是可以改善的 通过抑制电动汽车的释放。为了验证这一假设，在目标1中，我们将确定EV介导的贡献 内质网应激在促进受体基质和AML细胞化学保护性改变中的传递，以及 确定抑制外切体释放是否可以阻止这些影响。在目标2中，我们将确定EV与 BMPS对基质细胞的调节作用及阻断EV释放和BMP受体信号转导的作用 急性髓系白血病进展。我们的长期目标是回答有关AML细胞如何逃避的长期问题 化疗和开发新的治疗策略，以减少急性髓细胞白血病患者的耐药性。

Project Summary Acute Myelogenous Leukemia (AML) is an aggressive, genetically heterogeneous cancer—affecting both children and adults—that arises from abnormal myeloid cells in the bone marrow (BM). While many patients achieve remission following induction chemotherapy, the 5-year survival remains a dismal 25% due to relapse with increased resistance to cancer drugs. AML remodels the BM microenvironment, in part by releasing membrane-bound extracellular vesicles (EVs) that dysregulate recipient cells. We have found that EVs transfer endoplasmic reticulum-stress to stromal cells, leading to cell type-specific phenotypic changes that alter the cellular composition of the BM. Interestingly, these EVs were also found to contain bone morphorgenic proteins (BMP)—potent growth factors implicated in drug resistance and cancer progression. Currently little is known about how EV-mediated transmission of ER-stress and BMPs contribute to forming a chemo-protective niche. Multiple studies have shown that ER-stress can be transmitted between cells in the tumor microenvironment, contributing to drug resistance in solid tumor models. In the context of AML, we have found that EVs alone are sufficient to transmit ER-stress and activate the Unfolded Protein Response (UPR) pathway in recipient stromal cells. In vivo, AML cells exhibit marked UPR due to physiologic stress in the tumor microenvironment. We have found that the upregulation of the UPR pathway coincides with the increased expression and packaging of multiple BMP types onto EVs. Since both UPR and BMPs have been previously implicated in promoting cancer survival and drug resistance, we propose to study the role of EVs in transferring adaptive change to recipient BM cells to form a chemo-protective environment. Additionally, due to the mounting evidence that AML-EVs remodel the BM microenvironment, blocking EV biogenesis has become an obvious therapeutic target for AML. We hypothesize that EV-mediated transmission of Unfolded Protein Response and bone morphogenic proteins promotes adaptive changes contributing to drug resistance in AML, which can be ameliorated by inhibiting the release of EVs. To test this hypothesis, In AIM 1, we will identify the contribution of EV-mediated transmission of ER-stress in promoting chemo-protective changes in both recipient stromal and AML cells, and determine if inhibiting exosome release can prevent these effects. In Aim 2 we will determine how EV-associated BMPs dysregulate stromal cells, and examine the effect of blocking EV-release and BMP-receptor signaling on AML progression. Our long-term goal is to answer long standing questions about how AML cells evade chemotherapy and develop new therapeutic strategies to reduce drug resistance in patients with AML.