Biomechanical Regulation of Angiogenesis during Tumor Progression

项目摘要 在癌症进展过程中，血管生成被上调，以供应不断增加的代谢需求。 生长的肿瘤虽然靶向肿瘤相关的血管生成已成为许多肿瘤患者的治疗策略， 多年来，这些技术在许多癌症类型中表现出有限的有效性。我们认为这可能是由于 对肿瘤生物力学环境的了解有限。近期癌症相关 成纤维细胞（CAF）已被证明是负责肿瘤周围环境的关键调节因子， 分泌几种控制血管生成和转移的生长因子。CAFs表现出肌纤维母细胞样的 表型，α-平滑肌肌动蛋白和蜗牛1增加。我们假设CAF产生的 生物力学应变的增加增强了肿瘤中的尖端细胞活化并驱动血管生成 微环境我们的初步工作已经证明，CAF的生物力学活动是直接相关的， 这些细胞在血管生长的体外模型中的血管形成潜力，以及抑制这些细胞的血管形成潜力。 这些细胞中的机械传导途径废除了它们支持血管形成的能力， 网络.继续这项研究将进一步阐明生物力学在肿瘤进展过程中的作用， 并揭示了新的抗癌治疗策略的潜在靶点。在赠款的K99部分， 我们将（1）研究CAF生物力学在体内血管生成小鼠模型中的作用，（2）优化CAF生物力学模型。 用于血管生成研究的微流控平台，将允许分离和询问生物力学 参数拟议的微组织平台将是高度创新的，因为它允许独立控制 几个关键的生物力学特性。重要的是，这一阶段的赠款将补充PI的职业生涯 通过结合癌细胞生物学分析技术以及小鼠模型的培训进行开发 癌症进展在R 00部分的赠款，我们将研究如何内皮细胞反应， 利用先前开发的微组织模型从CAF获得机械线索。最后我们将调查 潜在的抗癌治疗策略，靶向CAF生物力学促进肿瘤的发展， 小鼠乳腺癌模型。最终，这项工作不仅对理解 癌症进展的生物力学，而且还开发了独特的体外微组织模型， 允许以真正原始的方式询问生物力学。培训、技术和方法 在此期间开发的赠款应开辟未来研究的几个新途径，并将允许PI 转变为完全独立的调查员

Project Summary During cancer progression, angiogenesis is upregulated to supply the ever-increasing metabolic demands of the growing tumor. While targeting tumor-associated angiogenesis has been a therapeutic strategy for many years, these techniques demonstrate limited effectiveness in many cancer types. We believe this may be due to limited understanding of the biomechanical environment of the tumor. Recently cancer-associated fibroblasts (CAFs) have been shown to be key regulators of the peritumoral environment responsible for secreting several growth factors that control angiogenesis and metastasis. CAFs exhibit a myofibroblast-like phenotype, with increases in alpha-smooth muscle actin and Snail1. We hypothesized that CAF-generated increases in biomechanical strains enhance tip cell activation and drive angiogenesis in the tumor microenvironment. Our initial work has demonstrated that CAF biomechanical activity is directly related to the vascularization potential of these cells in in vitro models of vascular growth, and that inhibiting the mechanotransductive pathways in these cells abrogated their ability to support the formation of blood vessel networks. Continuing this research will further elucidate the roles of biomechanics during tumor progression as well as reveal potential targets for novel anti-cancer therapeutic strategies. During the K99 portion of the grant, we will (1) investigate the role of CAF biomechanics in an in vivo angiogenic mouse model and (2) optimize a microfluidic platform for angiogenesis studies that will allow for isolation and interrogation of biomechanical parameters. The proposed microtissue platform will be highly innovative in that it allows for independent control of several key biomechanical properties. Importantly, this phase of the grant will complement the PI’s career development by incorporating training in cancer cell biology analysis techniques as well as mouse models of cancer progression. During the R00 portion of the grant, we will investigate how endothelial cells respond to mechanical cues from CAFs utilizing the microtissue model previously developed. Finally we will investigate potential anti-cancer therapeutic strategies targeting CAF biomechanical promotion of tumor development in a mouse model of breast cancer. Ultimately this work has significant implications for not only understanding biomechanics of cancer progression but also the development of a unique in vitro microtissue model that will permit interrogation of biomechanics in a truly original manner. The training, techniques, and approaches developed during this grant should open several new avenues for future studies and will allow the PI to transition into a fully-independent investigator.