Engineering the Cancer Microenvironment

项目总结/摘要 90%的癌症相关死亡是由于转移12，17。转移级联是一个复杂的系列 由癌细胞表型的变化引发的事件，通过一个过程产生侵袭性 被称为上皮-间充质转化（MET）7，14，15。一旦转移细胞进入循环系统 当肿瘤细胞进入系统时，细胞必须扩散到远处的组织中，导致继发性肿瘤的形成。当 当癌细胞到达新的组织时，它们的行为部分是由不溶性的 细胞外基质（ECM）蛋白在微环境10。目前，没有系统可以 重建这一序列的可溶性和不溶性信号事件，减缓发展的有效 治疗因此，在与Joerg Lahann博士的合作中，我建议开发一种工程癌症， 微环境，可用于评估特定微环境线索对癌细胞的影响 行为最近在Lahann实验室内开发了一种3D聚合物纤维写入系统， 具有图案化纤维结构的超多孔聚合物支架的制造。该系统能够精确 控制包括支架物理/机械性能在内的一系列特性， 用各种ECM蛋白的网络包被（在它们的3D生物活性构象中）。这些模块化 支架可以接种各种类型的细胞，从而能够研究细胞-细胞或细胞-基质的相互作用。 因此，这种可定制的平台技术可以被设计成模仿天然癌症的关键元素。 微环境在本提案的K99辅导阶段，机械性能和ECM 将调节组合物以模拟原发性和转移性肿瘤的元素。改变的效果 癌症微环境对癌细胞增殖、癌干细胞分布和表型都会产生影响， 评估。此外，这些环境还将用于培养从人乳腺癌细胞中获得的原代癌细胞。 胸腔积液细胞外基质成分对肿瘤干细胞分布和衰老的影响 将评价原始患者样本。癌症微环境的细胞成分和 还将研究转移前小生境。在R 00阶段过渡到独立，我将评估 工程化癌症微环境促进继发性肿瘤形成的体内功效。这 K99/R 00奖将使创建一个系统，可以重现转移性癌细胞侵袭， 体内，提供了一种手段，通过它可以更好地了解癌症的分子和细胞基础。如果 如果成功，该系统将为组合药物筛选提供平台技术，并可能导致 个性化癌症治疗的发展。在密歇根大学，我有机会接触到世界一流的 设施以及无与伦比的癌症研究领域的领导者集合。我召集了一个 尊敬的咨询委员会指导我的研究，并促进我向独立过渡。约尔格博士 Lahann，生物界面研究所所长，聚合物纤维和颗粒流体工艺专家 我将作为我的主要导师。密歇根大学校长Max Wicha博士 综合癌症中心和肿瘤发生领域的领导者，将担任我的共同导师。其他 我的指导团队的杰出成员包括Diane Simeone博士，翻译部主任， 肿瘤学项目和胰腺癌肿瘤发生专家加里卢克博士是分子生物学领域的专家。 成像系统和乳腺癌小鼠模型，以及Jan Stegemann博士， 3D组织工程环境和ECM信号传导。该奖项提供的机会， 与密歇根大学世界一流的设施和指导团队，将使我能够实现 我的短期目标是成为一名终身助理教授，以及我的长期目标， 开发技术，帮助患有侵袭性癌症的患者改善他们的 治疗结果和总体生活质量。

PROJECT SUMMARY/ABSTRACT 90% of cancer related deaths occur as a result of metastasis12,17. The metastatic cascade is a complex series of events initiated by changes of the cancer cell phenotype, giving rise to invasive properties through a process known as the epithelial-to-mesenchymal transition (MET)7, 14, 15. Once metastatic cells are in the circulatory system, the cells must extavasate into distant tissues, resulting in the formation of secondary tumors. When cancer cells arrive in the new tissues, their behavior is driven in part by the non-soluble signaling of extracellular matrix (ECM) proteins within the microenvironment10. Currently, no system exists that can recreate this sequence of soluble and non-soluble signaling events, slowing the development of effective therapies. Therefore, in collaboration with Dr. Joerg Lahann, I propose to develop an engineered cancer microenvironment that can be used to evaluate the effects of specific microenvironmental cues on cancer cell behavior. A 3D polymer fiber writing system has recently been developed within the Lahann lab that allows fabrication of hyper-porous polymer scaffolds with patterned fiber architectures. This system enables precise control over a range of characteristics including the scaffold physical/mechanical properties, and facilitates coating with networks of various ECM proteins (in their 3D biologically active conformations). These modular scaffolds can be seeded with a variety of cell types, enabling investigation of cell-cell or cell-matrix interactions. As such, this tailorable platform technology could be designed to mimic key elements of the native cancer microenvironment. During the mentored K99 phase of this proposal, the mechanical properties and ECM composition will be tuned to mimic elements of primary and metastatic tumors. The effect that changes in the cancer microenvironment has on cancer cell proliferation, cancer stem cell distribution, and phenotype will be evaluated. Furthermore, these environments will also be used to culture primary cancer cells obtained from pleural effusions. The effect of the ECM composition on cancer stem cell distribution and senescence of primary patient samples will be evaluated. The cellular components of the cancer microenvironment and the pre-metastatic niche will also be investigated. Transitioning into independence in the R00 phase, I will evaluate the in vivo efficacy of the engineered cancer microenvironments to promote secondary tumor formation. This K99/R00 award would enable the creation of a system that could recapitulate metastatic cancer cell invasion in vivo, providing a means by which the molecular and cellular basis of cancer can be better understood. If successful, this system will provide a platform technology for combinatorial drug screening and may lead to the development of personalized cancer therapies. At the University of Michigan, I have access to world-class facilities as well as an unparalleled collection of leaders in the field of cancer research. I have assembled an distinguished advisory committee to guide my research and facilitate my transition to independence. Dr. Joerg Lahann, Director of the Biointerfaces Institute and expert in fluid-based processes for polymer fiber and particle fabrication, will serve as my primary mentor. Dr. Max Wicha, Director of the University of Michigan Comprehensive Cancer Center and leader in the field of tumorigenesis, will serve as my co-mentor. Other distinguished members of my mentoring team include Dr. Diane Simeone, Director of the Translational Oncology Program and expert in pancreatic cancer tumorigenesis, Dr. Gary Luker, is an expert in molecular imaging systems and mouse models of breast cancer, and Dr. Jan Stegemann, expert in the development of 3D tissue engineered environments and ECM signaling. Opportunities provided by this award, in combination with the world-class facilities and mentoring team at the University of Michigan, would enable me to achieve both my short-term goal of becoming a tenure-track assistant professor, as well as my long-term goal of developing technologies that will help patients suffering from aggressive forms of cancer improve their therapeutic outcomes and overall quality of life.