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Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF
Hong-Wei Sun1,2, Wen-Chao Wu1, Hai-Tian Chen3
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
Abstract:
Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.
Insights
Glutamine deprivation in breast cancer cells boosts G-CSF and GM-CSF, mobilizing myeloid progenitor cells. These cells accumulate in tumors, becoming immunosuppressive myeloid-derived suppressor cells, promoting tumor progression.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Solid tumors face nutrient deprivation in their microenvironment.
- Cancer cells adapt to nutrient scarcity, but their interaction with the microenvironment is unclear.
- Understanding nutrient-deprived cancer cell roles is crucial for cancer progression insights.
Purpose of the Study:
- Investigate how glutamine-deprived cancer cells influence the tumor microenvironment.
- Identify mechanisms linking nutrient deprivation to immune cell mobilization.
- Determine the role of mobilized cells in breast cancer progression and immunosuppression.
Main Methods:
- Utilized mouse mammary cancer cells and tumor-bearing mouse models.
- Analyzed cytokine expression (G-CSF, GM-CSF) under glutamine deprivation.
- Examined the IRE1α-JNK pathway activation.
- Assessed hematopoietic progenitor cell (HPC) populations in bone marrow, spleen, and tumor tissue.
- Investigated bone marrow HPC-maintaining capacity and gene expression.
- Characterized tumor-infiltrating HPCs and their differentiation into myeloid-derived suppressor cells (MDSCs).
Main Results:
- Glutamine deprivation increased G-CSF and GM-CSF expression via the IRE1α-JNK pathway.
- Tumor progression led to decreased myeloid HPCs in bone marrow and increased HPCs in the spleen.
- Bone marrow's HPC-maintaining capacity was impaired, with reduced key gene expression.
- Mobilized HPCs accumulated in tumors and differentiated into immunosuppressive MDSCs.
- Glutamine starvation promotes MDSC generation in breast cancer.
Conclusions:
- Glutamine deprivation is a key driver of G-CSF and GM-CSF production in breast cancer.
- This process mobilizes hematopoietic progenitor cells, contributing to an immunosuppressive tumor microenvironment.
- Targeting glutamine metabolism or cytokine signaling may offer therapeutic strategies against breast cancer progression.
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