The effect of oxygen gradients on sarcoma invasiveness through dynamic collagen modulation

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Project 3 Summary Sarcoma is a malignant cancer derived from transformed cells of mesenchymal origin. Progression and metastasis of sarcomas is regulated by microenvironmental cues. Low intratumoral O2 (hypoxia) most dramatically increases pulmonary metastasis, and poor clinical outcomes, though we do not yet completely understand the critical effects of hypoxia on sarcoma cells and the microenvironment. Thus, defining how primary tumor cells respond to O2 in their microenvironment is essential for understanding metastasis and identification of novel therapeutic targets. Our recent work has shown that hypoxia promotes sarcoma metastasis, through induction of HIF1PLOD2 and the subsequent deposition of aberrant collagen that leads to distant metastasis. However, we do not yet know 1) how cell migration/invasion is altered in the presence of the O2 gradients that occur in tumors, 2) which collagen modifying-enzymes define the ECM, and 3) precisely how cells’ motility is modified in response to altered collagen structure in the microenvironment. The proposed studies address each of these unknowns. To model the O2-gradients that develop in tumors as they outgrow their vascular supply we developed novel O2- controlling hydrogels that can serve as 3D hypoxic microenvironments. We hypothesize that sarcoma cell invasion and migration is guided by increased O2 tension and facilitated by hypoxia-induced ECM remodeling. We will determine if O2 gradients regulate the direction, speed and distance of migrating sarcoma cells, how these factors depend on hypoxic ECM remodeling, focusing on collagen microstructure. Our approach will integrate mathematical modeling and experimental in vitro and in vivo models, linking O2-ECM-cellular invasion and migration in sarcomas. The specific aims are: (1) To determine sarcoma cell and tumor graft responses to spatial oxygen gradients; (2) To characterize collagen remodeling during sarcoma invasion under hypoxic gradients; (3) To determine how collagen fiber organization regulates hypoxic invasion and migration. The results of the experiments proposed here will identify the molecular and physical mechanisms underlying the initial steps of metastasis, invasion and migration, and develop predictive models for these mechanism, all leading to novel therapeutic targets.