Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth

Area of Science:

• Oncology
• Cancer Biology
• Tumor Microenvironment Research

Background:

• Reactive stromal cells within the tumor microenvironment (TME) influence cancer cell growth.
• Identifying stromal targets to enhance cancer cell vulnerability remains a significant challenge.
• Stromal cell metabolism is increasingly recognized as a critical factor in tumor progression.

Purpose of the Study:

• To identify novel mechanisms of reactive stromal cell reprogramming within the TME.
• To investigate the role of glutamine metabolism in stromal cells and its impact on cancer cells.
• To evaluate a co-targeting therapeutic strategy against stromal and cancer cell metabolism.

Main Methods:

• Analysis of metabolic reprogramming in reactive stromal cells, focusing on glutamine anabolic pathways.
• Utilized an orthotopic mouse model of ovarian carcinoma to study tumor growth and metastasis.
• Investigated the efficacy of co-targeting glutamine synthetase in stroma and glutaminase in cancer cells.

Main Results:

• Identified an upregulated glutamine anabolic pathway in reactive stromal cells, conferring metabolic flexibility.
• Demonstrated that dysfunctional stromal metabolism allows glutamine synthesis from noncanonical sources in nutrient-poor TME.
• Co-targeting stromal glutamine synthetase and cancer glutaminase significantly reduced tumor weight, nodules, and metastasis in mice.

Conclusions:

• Reactive stromal cells exhibit reprogrammed glutamine metabolism, contributing to cancer cell adaptation.
• Targeting stromal glutamine metabolism represents a viable strategy to sensitize cancer cells.
• A synthetic lethal approach co-targeting stromal and cancer cell glutamine metabolism offers therapeutic potential.