Fibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis

Area of Science:

• Oncology
• Cell Biology
• Metabolism

Background:

• Metastasis involves complex interactions between cancer cells and their surrounding stromal environment.
• Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that influence cancer progression.

Purpose of the Study:

• To investigate the bidirectional signaling between ovarian cancer cells and CAFs.
• To elucidate the metabolic mechanisms by which CAFs support cancer cell metastasis.

Main Methods:

• Utilized stable isotope labeling of amino acids in cell culture (SILAC) combined with quantitative label-free phosphoproteomics.
• Co-cultured ovarian cancer cells with human-derived CAFs.
• Performed in vivo experiments involving gene deletion and pharmacological inhibition.

Main Results:

• CAF co-culture promoted glycogenolysis and activated phosphoglucomutase 1 in cancer cells.
• Increased glycogen flux into glycolysis enhanced cancer cell proliferation, invasion, and metastasis.
• CAF-mediated glycogen mobilization was dependent on p38α MAPK activation.
• In vivo, p38α deletion in CAFs and glycogen phosphorylase inhibition reduced metastasis.

Conclusions:

• Glycogen serves as a crucial energy source for cancer cells during metastasis.
• Bidirectional signaling between CAFs and cancer cells, particularly involving p38α MAPK, drives metabolic reprogramming that supports metastatic growth.