Abstract A41: Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis

Abstract

Abstract Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF1α or PLOD2 expression disrupts collagen modification, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Biochemical analyses revealed that overexpression of HIF1α and PLOD2 in sarcoma cells alters collagen structure and organization. The increase in lysyl hydroxylation and concomitant loss of prolyl hydroxylation, promotes adherence of tumor cells, collagen-associated migration and tumor cell dissemination. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient tumors, and analysis of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Pharmacological inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF1α 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. Citation Format: T.S. Karin Eisinger-Mathason, Minsi Zhang, Qiu Qiong, Nicolas Skuli, Michael S. Nakazawa, Tatiana Karakasheva, Vera Mucaj, Jessica E.S. Shay, Lars Stangenberg, Ellen Pure, Sam S. Yoon, David G. Kirsch, M. Celeste Simon. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A41. doi:10.1158/1538-7445.CHTME14-A41