The role of GPSM3 in tumor-promoting emergency myelopoiesis

GPSM3在促肿瘤紧急骨髓细胞生成中的作用

• 批准号: 10115623
• 负责人: Bin Zhang
• 金额: $ 36.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115623
• 关键词: Adoptive Transfer; Bone Marrow; CCAAT-Enhancer-Binding Proteins; Cancer Control; Cell Differentiation process; Cell Line; Cell physiology; Cells; Colony-Stimulating Factors; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Emergency Situation; Event; Foundations; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Transcription; Goals; Hematopoietic; Human; Immunosuppression; Interleukin-6; Knowledge; Link; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Melanoma Cell; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Myelopoiesis; Output; Phenotype; Role; STAT1 gene; STAT3 gene; Signal Pathway; Signal Transduction; Signaling Protein; T-Lymphocyte; Testing; The Cancer Genome Atlas; Tissues; Tumor Immunity; Tumor Promotion; Tumor-Derived; Tumor-associated macrophages; Up-Regulation; Work; cytokine; gain of function; granulocyte; immunoregulation; loss of function; melanoma; migration; monocyte; neoplastic cell; new therapeutic target; novel; progenitor; recruit; response; selective expression; targeted cancer therapy; transcription factor; tumor; tumor growth; tumor microenvironment; tumor progression

Cancer progression is associated with a profound alteration in “emergency” myelopoiesis, leading to recruitment of mostly immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) and tumor- associated macrophages (TAM). In response to saturating amounts of tumor-induced colony-stimulating factors (CSFs), myeloid progenitors divide more frequently to sustain the hematopoietic output necessary to promote emergency myelopoiesis. Despite the knowledge about the involvement of cytokines and transcription factors in emergency myelopoiesis, the molecular mechanisms by which the cytokines induce transcriptional events regulating cancer-driven myelopoiesis remain largely unclear. Our preliminary data show that G protein signaling modulator-3 (GPSM3) is upregulated selectively in MDSC, either from tumor- bearing hosts or generated from bone marrow myeloid progenitors by the cytokines G-CSF, GM-CSF and IL-6. GPSM3-deficient myeloid progenitors display a reduced capacity to differentiate into granulocytes/monocytes following G-CSF/GM-CSF stimulation. Decreased accumulation of MDSC in GPSM3-deficient tumor-bearing hosts is linked with an altered expression in the key transcriptional mediators of myeloid progenitor commitment and differentiation to the granulocytic/monocytic lineage. Moreover, the immunoregulatory activity of both tumor-induced and cytokine-induced MDSC is dependent on GPSM3. These results have led to the novel hypothesis that GPSM3 is a master regulator of cancer-associated myelopoiesis and key driver of the differentiation of MDSCs for both immune suppression and tumor promotion. In this proposal, we will characterize further the phenotype and function of MDSC in the tumor microenvironment, and explore the signaling pathways implicated by GPSM3 in regulating MDSC differentiation and activation using both gain-of-function and loss-of- function approaches.

癌症进展与“紧急”骨髓生成的深刻改变相关，导致 募集大部分免疫抑制细胞，如骨髓来源的抑制细胞（MDSC）和肿瘤细胞， 相关巨噬细胞（TAM）。对饱和量的肿瘤诱导的集落刺激 由于骨髓造血因子（CSF）的作用，骨髓祖细胞分裂更频繁，以维持必要的造血输出。 促进紧急骨髓生成尽管有关于细胞因子参与的知识， 转录因子在紧急骨髓细胞生成中的作用，细胞因子诱导 调节癌症驱动的骨髓生成的转录事件在很大程度上仍不清楚。我们的初步数据显示 G蛋白信号转导调节因子3（GPSM 3）在MDSC中选择性上调，无论是来自肿瘤， 携带宿主或通过细胞因子G-CSF、GM-CSF和 IL-6。GPSM 3缺陷型髓系祖细胞显示出分化为 在G-CSF/GM-CSF刺激后，中性粒细胞/单核细胞。MDSC蓄积减少， GPSM 3缺陷型肿瘤宿主与关键转录介质的表达改变有关 髓系祖细胞定型和分化为粒细胞/单核细胞谱系。而且 肿瘤诱导的MDSC和苦参碱诱导的MDSC的免疫调节活性都依赖于GPSM 3。 这些结果提出了新的假设，即GPSM 3是癌症相关蛋白的主要调节因子 骨髓生成和MDSC分化的关键驱动因素，用于免疫抑制和肿瘤 推广.在这个建议中，我们将进一步表征MDSC在肿瘤中的表型和功能 微环境，并探讨GPSM 3参与调节MDSC的信号通路 使用功能获得和功能丧失方法两者的分化和活化。

项目成果

The Janus Face of IL-33 Signaling in Tumor Development and Immune Escape.

• DOI: 10.3390/cancers13133281
• 发表时间: 2021-06-30
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Choi MR;Sosman JA;Zhang B
• 通讯作者: Zhang B

Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer.

• DOI: 10.1158/0008-5472.can-17-2460
• 发表时间: 2018-04-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Li L;Wang L;Li J;Fan Z;Yang L;Zhang Z;Zhang C;Yue D;Qin G;Zhang T;Li F;Chen X;Ping Y;Wang D;Gao Q;He Q;Huang L;Li H;Huang J;Zhao X;Xue W;Sun Z;Lu J;Yu JJ;Zhao J;Zhang B;Zhang Y
• 通讯作者: Zhang Y