Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.

Journal Article (Journal Article)

UNLABELLED: Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. SIGNIFICANCE: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.

Full Text

Duke Authors

Cited Authors

  • Eisinger-Mathason, TSK; Zhang, M; Qiu, Q; Skuli, N; Nakazawa, MS; Karakasheva, T; Mucaj, V; Shay, JES; Stangenberg, L; Sadri, N; Puré, E; Yoon, SS; Kirsch, DG; Simon, MC

Published Date

  • October 2013

Published In

Volume / Issue

  • 3 / 10

Start / End Page

  • 1190 - 1205

PubMed ID

  • 23906982

Pubmed Central ID

  • PMC3822914

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0118


  • eng

Conference Location

  • United States