Investigation of STAT2 Signaling in the tumor microenvironment

摘要 肿瘤细胞和基质细胞之间的细胞间通讯，其主要成分是 成纤维细胞在肿瘤的生长、发展和转移中起着重要作用。这项建议 目的是研究STAT2信号在结直肠之间的信息交换中的作用 肿瘤微环境中的癌(CRC)细胞和间质癌相关成纤维细胞(CAF)。 我们的初步研究表明，STAT2的高表达与低存活率之间的临床相关性 STAT2与CAFS标志物呈正相关。结直肠癌的肿瘤活检结果分析 2例患者肿瘤及周围间质中STAT2蛋白升高。两种动物的研究 结直肠癌的模型显示，STAT2具有致瘤作用。RNA-Seq分析揭示了一个转录签名 与肿瘤相关的成纤维细胞有关。此外，我们发现STAT2促进了 肿瘤细胞的增殖和侵袭。同时，我们发现，在正常情况下，EGF的诱导表达 STAT2缺陷性肿瘤条件培养液诱导成纤维细胞效果不佳 细胞。考虑到这些观察，我们假设STAT2在 肿瘤和CAF导致结直肠癌疾病进展。目标是：(1)确定是否 固有的肿瘤STAT2信号导致正常成纤维细胞重新编程为CAF以促进肿瘤 生长和(2)确定正常成纤维细胞中的STAT2信号是否导致它们转化为 CAFS可促进肿瘤生长。这项研究的完成将揭示STAT2信号的重要性 在肿瘤微环境中作为通信轴(单向与双向)之间 肿瘤细胞和CAF，以促进肿瘤的生长、迁移和侵袭。 意义：靶向治疗与化疗相结合治疗晚期结直肠癌 取得了不大的成功。STAT2信号在肿瘤中的致癌作用 微环境可能导致新的治疗策略的发展。如果我们的研究结果是 揭示STAT2在肿瘤细胞间通讯的建立中起着动态作用 微环境，我们的发现将支持抑制STAT2信号作为一种治疗手段的理论基础 转移性结直肠癌的介入治疗。

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.