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

项目3摘要 肉瘤是由间充质来源的转化细胞衍生的恶性癌症。进展和 肉瘤的转移受微环境因素的调节。低肿瘤内O2（缺氧） 显著增加肺转移，临床结果不佳，尽管我们还没有完全 了解缺氧对肉瘤细胞和微环境的关键影响。因此，定义主要 肿瘤细胞在其微环境中对O2的反应对于理解转移和识别是必不可少的 新的治疗靶点。 我们最近的研究表明，低氧通过诱导HIF 1 α-PLOD 2促进肉瘤转移 以及导致远处转移的异常胶原蛋白的后续沉积。然而，我们还没有 了解1）在肿瘤中存在O2梯度的情况下，细胞迁移/侵袭如何改变，2） 胶原蛋白修饰酶定义ECM，以及3）细胞的运动性如何响应于 改变了微环境中的胶原蛋白结构拟议的研究解决了这些未知数中的每一个。到 为模拟肿瘤生长超过其血管供应时产生的氧气梯度，我们开发了新的氧气- 控制可以作为3D缺氧微环境的水凝胶。 我们假设肉瘤细胞的侵袭和迁移是由氧气张力增加引导并促进的。 缺氧诱导的ECM重塑。我们将确定O2梯度是否调节方向，速度和 迁移肉瘤细胞的距离，这些因素如何依赖于缺氧ECM重塑，重点是胶原蛋白 微观结构我们的方法将整合数学建模和实验在体外和体内模型， 连接肉瘤中的O2-ECM-细胞侵袭和迁移。具体目的是：（1）确定肉瘤 细胞和肿瘤移植物对空间氧梯度的反应;（2）表征胶原重塑过程中 探讨胶原纤维组织如何调节低氧对肉瘤侵袭的影响 入侵和迁移。本文提出的实验结果将确定分子和物理 转移，侵袭和迁移的初始步骤的潜在机制，并开发预测模型 这些机制，都导致新的治疗目标。

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.