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) 仍然是儿科肿瘤学的主要挑战，占所有儿科癌症死亡率的 15%，这种侵袭性胚胎恶性肿瘤的总体 5 年生存率低于 50%。与 90% 的实体瘤一样，NB 死亡的主要原因是复发的耐药性疾病。 NB 治愈率的显着提高将需要新的生物学特异性方法，因为在超过一半的病例中，最大耐受剂量的化疗仍然失败。癌症干细胞（CSC）模型现在表明，治疗失败和复发通常是由一小部分自我更新的肿瘤起始细胞的耐药亚群引起的。我们的治疗目标是 将抗 CSC 疗法与当前的化疗方法相结合，以改善初始药物反应并预防复发性转移性疾病。初步数据：我们最近展示了基于 CD114（粒细胞集落刺激因子 (G-CSF) 的表面受体）表达的高致瘤性亚群的分离和表征，该亚群满足肿瘤起始 CSC 的主要表型要求。在 3 个化疗周期后切除的 NB 肿瘤中，该肿瘤亚群在化疗后高度富集（高达 10 倍），并且具有基因表达、microRNA 表达和表观遗传特征，概括了 iPSC（诱导多能干细胞）和 ESC（胚胎干细胞）的基因表达、microRNA 表达和表观遗传特征。干细胞）。通过磷酸化激活 STAT3 (pSTAT3) 是 G-CSF 配体与其受体 (CD114) 结合的典型下游效应子。 pSTAT3 在调节正常和恶性干细胞群的维持方面发挥着核心作用，部分是通过参与重编程和上皮间质转化 (EMT) 的 microRNA 的转录调节。我们证明在 CD114+ CSC 样细胞中，G-CSF 依赖性 pSTAT3 激活导致 STAT3 靶 microRNA 表达增加。我们还证明 CSFR3 基因（编码 CD114）是 pSTAT3 的直接转录靶标，表明维持该受体表达的反馈环。因此，我们假设如下：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) 直接或通过 G-CSF/STAT3 通路抑制靶向 CD114+ 细胞将限制肿瘤增殖 和转移的发展。 C) 同时靶向神经母细胞瘤中的 CD114+ 和 CD114- 亚群应通过防止 CD114+ 前体细胞再生 CD114- 细胞来显着增强化疗效果。在具体目标 1 和 2 中，我们将使用几种独立的方法（抗受体抗体、JAK/STAT 小分子抑制剂）阻断 CD114+ NB 细胞中的 G-CSF/STAT3 轴，以确定 G-CSF 信号传导在 CD114+ 中的作用驱动NB肿瘤发生和转移。在目标 3 中，我们将确定 STAT3 靶向 microRNA 如何促进 CD114+ 细胞的干性表型。