Abstract
<div>Abstract<p>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 <i>LSL-Kras<sup>G12D/+</sup>; Trp53<sup>fl/fl</sup></i> murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α–deficient tumors, and analysis of human sarcomas reveals elevated <i>HIF1A</i> and <i>PLOD2</i> 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.</p><p><b>Significance:</b> 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, specifically the collagen-modifying enzyme PLOD2. <i>Cancer Discov; 3(10); 1190–1205. ©2013 AACR</i>.</p><p>See related commentary by Vanharanta and Massagué, p. 1103</p><p>This article is highlighted in the In This Issue feature, p. 1083</p></div>
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