Investigation of STAT2 Signaling in the tumor microenvironment

总结 肿瘤细胞和基质细胞之间的细胞间通讯，其主要成分是 成纤维细胞在肿瘤生长、癌症进展和转移中起重要作用。这项建议 目的是研究STAT 2信号在结直肠和结肠癌之间交流中的作用。 肿瘤微环境中的CRC细胞和间质癌相关成纤维细胞（CAF）。 我们的初步研究表明，STAT 2高表达和低生存率之间的临床相关性， STAT 2与CAFs标志物呈正相关。结直肠癌活检结果分析 患者的肿瘤和周围间质中的STAT 2蛋白升高。两种动物的研究 CRC模型显示STAT 2是致瘤性的。RNA-Seq分析揭示了一个转录特征 与肿瘤相关的成纤维细胞有关。此外，我们发现STAT 2促进了 肿瘤细胞的增殖和侵袭。与此同时，我们发现正常人表皮生长因子表达的诱导， 在与来自STAT 2缺陷肿瘤的条件培养基孵育后，成纤维细胞诱导较差 细胞考虑到这些观察结果，我们假设STAT 2介导了 肿瘤和CAF导致CRC疾病进展。目的是：（1）确定 内源性肿瘤STAT 2信号传导导致正常成纤维细胞重编程为CAF， （2）确定正常成纤维细胞中的STAT 2信号传导是否导致它们转化为成纤维细胞。 CAF促进肿瘤生长。这项研究的完成将揭示STAT 2信号传导的重要性。 在肿瘤微环境中作为通信轴（单向与双向）， 肿瘤细胞和CAF以增强肿瘤生长、迁移和侵袭。 意义：靶向治疗与化疗联合治疗晚期结直肠癌， 取得了一定的成功。描述STAT 2信号在肿瘤中的致癌作用 微环境的变化可能导致新的治疗策略的发展。如果我们的研究结果 揭示了STAT 2在肿瘤细胞间通讯的建立中起着动态作用 微环境，我们的研究结果将支持抑制STAT 2信号传导作为治疗方法的理论基础 治疗转移性CRC的干预措施。

SUMMARY Intercellular communication between tumor cells and stromal cells of which major components are fibroblasts play a significant role in tumor growth, cancer progression and metastasis. This proposal aims to investigate the role of STAT2 signaling in the exchange of communication between colorectal cancer (CRC) cells and stromal cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Our preliminary show that a clinical correlation between high STAT2 expression and poor survival as well as a positive correlation between STAT2 and markers of CAFs. Analysis of tumor biopsies of CRC patients showed elevated STAT2 protein in the tumor and surrounding stroma. Studies in two animal models of CRC reveal that STAT2 is tumorigenic. RNA-Seq analysis exposed a transcriptional signature associated with tumor associated fibroblasts. Furthermore, we found that STAT2 facilitates the proliferation and invasion of tumor cells. In parallel, we found that induction of EGF expression in normal fibroblasts was poorly induced after incubation with conditioned medium from STAT2 deficient tumor cells. Given these observations, we postulate that STAT2 mediates the crosstalk between the tumor and CAFs leading to CRC disease progression. The objective is to: (1) Determine whether intrinsic tumor STAT2 signaling leads to reprogramming of normal fibroblasts to CAFs to promote tumor growth and (2) Determine whether STAT2 signaling in normal fibroblasts leads to their conversion to CAFs to enhance tumor growth. Completion of this study will reveal the importance of STAT2 signaling in the tumor microenvironment as the communication axis (unidirectional vs. bidirectional) between tumor cells and CAFs to enhance tumor growth, migration, and invasion. Significance: Treatment of advanced CRC by combining targeted therapies with chemotherapy has produced modest success. Delineating the oncogenic role of STAT2 signaling in the tumor microenvironment may lead to the development of novel therapeutic strategies. If results from our study reveal that STAT2 plays a dynamic role in the establishment of cell-to-cell communication in the tumor microenvironment, our findings will support a rationale to inhibit STAT2 signaling as a therapeutic intervention for the treatment of metastatic CRC.