Targeting the G-CSF/STAT3 signaling pathway in neuroblastoma cancer stem cells

靶向神经母细胞瘤干细胞中的 G-CSF/STAT3 信号通路

• 批准号: 8696457
• 负责人: JASON M SHOHET
• 金额: $ 32.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-09 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696457
• 关键词: Accounting; Automobile Driving; Binding; CSF3 gene; CSF3R gene; Cause of Death; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Child; Complex; Data; Development; Diagnosis; Disease; Disease Resistance; Drug resistance; Embryonic Development; Engraftment; Epigenetic Process; Epithelial; Equilibrium; Exposure to; Fc Receptor; Feedback; Founder Generation; Ganglia; Gene Expression; Genes; Genetic Transcription; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte Colony-Stimulating Factor Receptors; Growth Factor; Hematogenous; Hematopoietic Cell Growth Factors; Human; Immune; Inflammatory; Interleukin-1 beta; Interleukin-6; Ligand Binding; Literature; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Maximum Tolerated Dose; Mesenchymal; Metastatic/Recurrent; MicroRNAs; Modeling; Modification; Mus; Natural regeneration; Neoplasm Metastasis; Neural Crest; Neural Crest Cell; Neuroblastoma; Neurons; Pathway interactions; Patients; Pediatric Oncology; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Polycomb; Population; Process; Publishing; Receptor Gene; Recurrence; Recurrent disease; Regulation; Relapse; Relative (related person); Resected; Resistance; Role; STAT3 gene; Signal Pathway; Signal Transduction; Solid Neoplasm; Stem cells; Surface; Survival Rate; Sympathetic Nervous System; Therapeutic; Tissues; Transcriptional Regulation; Treatment Failure; Tumorigenicity; base; cancer stem cell; chemotherapy; chromatin modification; clinically relevant; cytokine; embryonic stem cell; epithelial to mesenchymal transition; high risk; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; mortality; neuroblastoma cell; novel; prevent; progenitor; promoter; public health relevance; receptor; receptor expression; response; self-renewal; small molecule; stem; stem cell population; stem cell therapy; stemness; transcription factor; tumor; tumor initiation; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): High-risk neuroblastoma (NB) remains a major challenge in pediatric oncology accounting for 15% of all pediatric cancer mortality with an overall 5-year survival of less than 50% for this aggressive embryonal malignancy. As with 90% of all solid tumors, the primary cause of death for NB is relapsed drug-resistant disease. Significant improvements in cure rates for NB will require novel biologically specific approaches since chemotherapy at maximal tolerated doses still fails in over half of theses cases. Models of cancer stem cells (CSCs) now suggest that treatment failure and relapse is often driven by a small drug-resistant subpopulation of self-renewing tumor initiating cells. Our therapeutic goal is to combine anti-CSC therapies with current chemotherapy approaches to both improve initial drug responses and prevent recurrent metastatic disease. Preliminary Data: We have recently demonstrated the isolation and characterization of a highly tumorigenic subpopulation based on the expression of CD114 (the surface receptor for granulocyte colony-stimulating factor (G-CSF)), which fulfills the major phenotypic requirements for tumor initiating CSCs. This tumor subpopulation is highly enriched (up to 10-fold) after chemotherapy in NB tumors resected after 3 cycles of chemotherapy and has gene expression, microRNA expression, and epigenetic profiles which recapitulate those of iPSCs (induced pluripotent stem cells) and ESCs (embryonic stem cells). STAT3 activation through phosphorylation (pSTAT3) is the canonical downstream effector of G-CSF ligand binding to its receptor (CD114). pSTAT3 has a central role in regulating the maintenance of normal and malignant stem cell populations in part through transcriptional regulation of microRNAs involved in reprogramming and epithelial-mesenchymal transitions (EMT). We demonstrate within the CD114+ CSC-like cells, G-CSF dependent pSTAT3 activation results in increased expression of STAT3 target microRNAs. We also demonstrate that the CSFR3 gene (encoding CD114) is a direct transcriptional target of pSTAT3, suggesting a feedback loop for maintenance of expression of this receptor. We therefore hypothesize the following: a) the G-CSF/STAT3 signaling axis promotes the maintenance, drug resistance and metastatic potential of CD114+ NB cells b) Targeting CD114+ cells, either directly or via G- CSF/STAT3 pathway inhibition will limit tumor proliferation and the development of metastasis. C) Concomitant targeting of both the CD114+ and CD114- subpopulations in neuroblastoma should significantly augment chemotherapies by preventing regeneration of CD114- cells from the CD114+ precursors. In Specific Aims 1 and 2, we will block the G-CSF/STAT3 axis in CD114+ NB cells using by several independent approaches (anti-receptor antibody, JAK/STAT small molecule inhibitors) to determine the role of G-CSF signaling in CD114+ driven NB tumorigenesis and metastasis. In Aim 3 we will determine how STAT3 target microRNAs contribute to the stemness phenotype of CD114+ cells.

描述（由申请人提供）：高危神经母细胞瘤（NB）仍然是小儿肿瘤学的主要挑战，占所有儿科癌症死亡率的15％，总5年生存率少于50％，而这种侵略性的胚胎恶性肿瘤。与所有实体瘤的90％一样，NB的主要死亡原因是耐药性疾病。 NB的治疗速率的显着提高将需要新颖的生物学特异性方法，因为在超过一半的情况下，最大耐受剂量的化学疗法仍然失败。癌症干细胞（CSC）的模型现在表明，治疗失败和复发通常是由对自我更新肿瘤引发细胞的抗药性亚群体驱动的。我们的治疗目标是 将抗CSC疗法与当前的化学疗法方法结合起来，以改善初始药物反应并防止复发转移性疾病。初步数据：我们最近证明了基于CD114（粒细胞刺激因子的表面受体（G-CSF））的表达的高度致瘤亚群的分离和表征，这满足了Tumor启动CSC的主要表型需求。在化疗3循环后切除的NB肿瘤后，该肿瘤亚群高度富集（最多10倍），并具有基因表达，microRNA表达和表观遗传谱，这些谱图概括了IPSC（诱导的多能干细胞）和ESCS（ESCS）和ESCS（胚胎干细胞）。 STAT3通过磷酸化（PSTAT3）激活是G-CSF配体与其受体结合的典型下游效应子（CD114）。 PSTAT3在调节正常和恶性干细胞群体的维持中具有核心作用，部分通过转录调节重编程和上皮 - 间质转变（EMT）的microRNA。我们在CD114+ CSC样细胞中证明了G-CSF依赖性PSTAT3激活导致STAT3靶MicroRNA的表达增加。我们还证明了CSFR3基因（编码CD114）是PSTAT3的直接转录靶标，这表明有用于维持该受体表达的反馈回路。因此，我们假设以下内容：a）G-CSF/STAT3信号轴促进CD114+ NB细胞的维持，耐药性和转移潜力b）靶向CD114+细胞（直接或通过G-CSF/STAT3途径）限制肿瘤的抑制作用 以及转移的发展。 c）神经母细胞瘤中CD114+和CD114-亚群的同时靶向应通过防止CD114+前体中CD114-细胞再生来显着增强化学疗法。在特定的目标1和2中，我们将使用几种独立方法（抗受体抗体，JAK/Stat小分子抑制剂）来阻止CD114+ NB细胞中的G-CSF/STAT3轴，以确定G-CSF信号在CD114+ CD114+驱动的NB肿瘤和转移中的作用。在AIM 3中，我们将确定STAT3目标microRNA如何促进CD114+细胞的干性表型。