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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.

总结