The role of GPSM3 in tumor-promoting emergency myelopoiesis

癌症进展与“紧急”骨髓生成的深刻变化有关，导致 主要是免疫抑制细胞的招募，如髓系来源的抑制细胞(MDSC)和肿瘤- 相关巨噬细胞()。对饱和数量的肿瘤诱导的集落刺激的响应 因子(CSF)，髓系祖细胞分裂更频繁，以维持必要的造血输出 促进急诊骨髓再生。尽管有关于细胞因子和 转录因子在急诊骨髓生成中的作用，细胞因子诱导的分子机制 调控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蛋白信号调节剂-3(GPSM3)在MDSC中选择性上调，无论是来自肿瘤还是来自于 承载宿主或由骨髓髓系祖细胞通过细胞因子G-CSF、GM-CSF和 IL-6。缺乏GPSM3的髓系祖细胞分化为 G-CSF/GM-CSF刺激后的粒细胞/单核细胞。减少MDSC在体内的积累 GPSM3缺陷的荷瘤宿主与关键转录介质的表达变化有关 髓系祖细胞向粒/单核细胞谱系的承诺和分化。此外， 肿瘤诱导和细胞因子诱导的MDSC的免疫调节活性均依赖于GPSM3。 这些结果导致了一种新的假设，即GPSM3是癌症相关的主调节因子 免疫抑制和肿瘤MDSCs的骨髓生成及其分化的关键因素 升职。在这个方案中，我们将进一步表征肿瘤中多药耐药干细胞的表型和功能。 微环境，并探讨GPSM3调控MDSC的信号通路 使用功能获得和功能丧失两种方法进行分化和激活。

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.