A feedback loop between hypoxia and matrix stress relaxation increases oxygen-axis migration and metastasis in sarcoma

Upregulation of collagen matrix cross-linking directly increases its ability to relieve stress under the constant strain imposed by solid tumor, a matrix property termed stress relaxation. However, it is unknown how rapid stress relaxation in response to increased strain impacts disease progression in a hypoxic environment. In this study, we demonstrated that hypoxia-induced expression of the cross-linker procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) in sarcomas resulted in increased lung metastasis. Short stress relaxation times led to increased cell migration along a hypoxic gradient in 3D collagen matrices, and rapid stress relaxation upregulated PLOD2 expression via TGFβ-SMAD2- signaling, forming a feedback loop between hypoxia and the matrix. Inhibition of this pathway led to a decrease in migration along the hypoxic gradients. In vivo, sarcoma primed in a hypoxic matrix with short stress relaxation time enhanced collagen fiber size and tumor density and increased lung metastasis. High expression of PLOD2 correlated with decreased overall survival in sarcoma patients. Using a patient-derived sarcoma cell line, we developed a predictive platform for future personalized studies and therapeutics. Overall, these data show that the interplay between hypoxia and matrix stress relaxation amplifies PLOD2, which in turn accelerates sarcoma cell motility and metastasis.

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