Investigation of STAT2 Signaling in the tumor microenvironment

肿瘤微环境中 STAT2 信号传导的研究

基本信息

批准号：
10661993
负责人：
ANA M GAMERO
金额：
$ 7.93万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661993
关键词：
Acceleration Address Affect Animal Model Applications Grants Biological Biopsy CRISPR/Cas technology Cancer Relapse Cell Communication Cell Extracts Cells Chemicals Clinical Coculture Techniques Colon Colon Carcinoma Colorectal Cancer Communication Computer Analysis Conditioned Culture Media Data Data Set Development Disease Disease Progression EGF gene Enabling Factors Epidermal Growth Factor Receptor Exposure to Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Gene Expression Gene Expression Profile Genes Growth Human In Vitro Incidence Incubated Interferon Type I Invaded Investigation Knowledge MAP Kinase Gene Malignant Neoplasms Measures Mediating Mediator Molecular NF-kappa B Neoplasm Metastasis Oncogenic PIK3CG gene Phenotype Platelet-Derived Growth Factor Play Proliferating Proteins Recurrent Malignant Neoplasm Resistance Role STAT2 gene STAT3 gene Signal Pathway Signal Transduction Stat2 protein Stromal Cells System TNF gene The Cancer Genome Atlas Therapeutic Intervention Transforming Growth Factor beta Tumor Burden Tumor Cell Invasion Tumor Promotion Tumorigenicity Woman antitumor effect cancer biomarkers cancer cell cancer recurrence cancer therapy chemotherapy clinically relevant colon cancer patients colon carcinogenesis colon tumorigenesis in vivo intercellular communication men metastatic colorectal migration mortality multiplex assay neoplastic cell novel therapeutic intervention phenotypic biomarker prognostic indicator programs success targeted treatment transcription factor transcriptome sequencing tumor tumor growth tumor initiation tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

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.

概括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、癌症进展和转移中发挥重要作用。这个提议旨在研究STAT2信号在结直肠癌之间的通讯交换中的作用肿瘤微环境中的癌细胞（CRC）和间质癌相关成纤维细胞（CAF）。我们的初步结果表明，STAT2 高表达与生存率低之间存在临床相关性： STAT2 与 CAF 标记物之间呈正相关。 CRC 肿瘤活检分析患者的肿瘤和周围基质中 STAT2 蛋白升高。对两种动物的研究 CRC 模型表明 STAT2 具有致瘤性。 RNA-Seq 分析揭示了转录特征与肿瘤相关成纤维细胞有关。此外，我们发现 STAT2 促进肿瘤细胞的增殖和侵袭。与此同时，我们发现正常细胞中 EGF 表达的诱导与 STAT2 缺陷肿瘤的条件培养基一起孵育后，成纤维细胞的诱导效果较差细胞。鉴于这些观察结果，我们假设 STAT2 介导肿瘤和 CAF 导致 CRC 疾病进展。目标是： (1) 确定是否内在的肿瘤 STAT2 信号传导导致正常成纤维细胞重编程为 CAF，从而促进肿瘤发生 (2) 确定正常成纤维细胞中的 STAT2 信号传导是否导致其转化为 CAF 促进肿瘤生长。这项研究的完成将揭示 STAT2 信号传导的重要性以肿瘤微环境作为通信轴（单向与双向）肿瘤细胞和 CAF 增强肿瘤生长、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已取得进展取得了一定的成功。描述 STAT2 信号在肿瘤中的致癌作用微环境可能会导致新的治疗策略的发展。如果我们的研究结果揭示 STAT2 在肿瘤细胞间通讯的建立中发挥动态作用微环境，我们的研究结果将支持抑制 STAT2 信号传导作为治疗方法的基本原理转移性结直肠癌的治疗干预。