Glutamine-Directed Migration of Cancer-Activated Fibroblasts Facilitates Epithelial Tumor Invasion

Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAP) that facilitate epithelial tumor cell invasion. We show here that CAFs and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of utaminase. Glutamine dependence drove CAF migration toward this amino acid when cultured in low glutamine conditions. CAR also invaded a Mangel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were cocultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation, which involved the TGF beta/Snaill signaling axis. CAFs moving toward Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells toward nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis. Significance: Cancer-associated fibroblasts migrate and invade toward free glutamine and facilitate invasion of tumor epithelial cells, accounting for their movement away from the hostile conditions of the tumor towards nutrient-rich adjacent tissues. [GRAPHICS] .

Automated summary

Our study reveals that cancer-associated fibroblasts display a higher dependency on glutamine than epithelial tumor cells, leading to increased sensitivity to glutaminase inhibition. Furthermore, our results demonstrate that glutamine deprivation promotes CAF migration and invasion, facilitating the movement of tumor epithelial cells towards nutrient-rich territories. This novel molecular mechanism highlights how metabolic stress enhances invasion and metastasis in cancer.