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A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma.

Publication ,  Journal Article
Lewis, DM; Pruitt, H; Jain, N; Ciccaglione, M; McCaffery, JM; Xia, Z; Weber, K; Eisinger-Mathason, TSK; Gerecht, S
Published in: Cancer research
April 2019

Upregulation of collagen matrix crosslinking 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. Previously, it has been demonstrated that hypoxia-induced expression of the crosslinker procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), in sarcomas has resulted in increased lung metastasis. Here, we show that 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 patients with sarcoma. 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. SIGNIFICANCE: These findings demonstrate that mechanical (stress relaxation) and chemical (hypoxia) properties of the tumor microenvironment jointly accelerate sarcoma motility and metastasis via increased expression of collagen matrix crosslinker PLOD2.

Duke Scholars

Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

April 2019

Volume

79

Issue

8

Start / End Page

1981 / 1995

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta1
  • Stress, Mechanical
  • Smad2 Protein
  • Sarcoma
  • Rheology
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Oxygen
 

Citation

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Lewis, D. M., Pruitt, H., Jain, N., Ciccaglione, M., McCaffery, J. M., Xia, Z., … Gerecht, S. (2019). A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma. Cancer Research, 79(8), 1981–1995. https://doi.org/10.1158/0008-5472.can-18-1984
Lewis, Daniel M., Hawley Pruitt, Nupur Jain, Mark Ciccaglione, J Michael McCaffery, Zhiyong Xia, Kristy Weber, TS Karin Eisinger-Mathason, and Sharon Gerecht. “A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma.Cancer Research 79, no. 8 (April 2019): 1981–95. https://doi.org/10.1158/0008-5472.can-18-1984.
Lewis DM, Pruitt H, Jain N, Ciccaglione M, McCaffery JM, Xia Z, et al. A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma. Cancer research. 2019 Apr;79(8):1981–95.
Lewis, Daniel M., et al. “A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma.Cancer Research, vol. 79, no. 8, Apr. 2019, pp. 1981–95. Epmc, doi:10.1158/0008-5472.can-18-1984.
Lewis DM, Pruitt H, Jain N, Ciccaglione M, McCaffery JM, Xia Z, Weber K, Eisinger-Mathason TSK, Gerecht S. A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma. Cancer research. 2019 Apr;79(8):1981–1995.

Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

April 2019

Volume

79

Issue

8

Start / End Page

1981 / 1995

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Microenvironment
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta1
  • Stress, Mechanical
  • Smad2 Protein
  • Sarcoma
  • Rheology
  • Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
  • Oxygen