Role of the physical microenvironment in tumor cell migration and the cell cycle

描述（申请人提供）：近年来，癌症已超过心脏病，成为85岁以下美国人死亡的主要原因。特别是，乳腺癌是美国癌症相关死亡的第二大原因，并且通常导致骨、肺和肝脏中的继发性转移性肿瘤部位。肿瘤的进展和转移涉及两个基本的细胞过程：通过间质组织的细胞迁移和原发肿瘤和远端转移部位的细胞分裂。在这些过程中，细胞受到复杂的三维环境的影响，这些环境在生物学和物理学上都有变化。在这个提议中，总的目标是评估细胞体积和极性是如何 当细胞受到不同程度的物理限制和/或基质弹性时，在迁移和分裂过程中受到调节。我们将使用微加工设备，细胞工程技术，高分辨率相衬和激光扫描共聚焦时移显微镜的组合来实现这一目标。我们假设乳腺癌细胞微环境的物理特性在迁移和细胞周期过程中调节细胞体积和极性。提出了两个具体的目标来解决这一假设：（1）阐明细胞迁移和体积调节的分子机制，以响应有限的微环境中的渗透压休克;和（2）评估的限制和微环境弹性的影响，对细胞周期的空间和时间的调节。本项目的长期目标是：（1）在基础科学水平上，帮助我们理解细胞体积和极性在有限微环境中迁移和分裂过程中是如何调节的;（2）提供最终可用于开发新的治疗策略以控制乳腺癌细胞增殖和转移的知识，（3）为我提供癌症生物物理学领域的实验和理论培训，这将是我未来作为独立研究人员的职业生涯所必需的;以及（4）通过资助和手稿写作培训，指导研究生和本科生，公开演讲，与未来的合作者建立联系。根据奖学金计划的活动包括原创研究（60%的时间）;手稿准备（10%）;资助写作（10%）;癌症生物学，研究领导和负责任的研究行为（5%）的正式课程工作;出席专业会议（5%）;参加我们实验室和合作者的实验室小组会议（5%）;指导博士。和本科生（2%）;参加部门研讨会（2%）;和博士后期刊俱乐部的参与（1%）。在完成这项研究金下拟议的活动时，我将 准备好开始一个独立的教师生涯，并将有知识基础和技能，以解决与癌症有关的生物学问题，使用生物工程策略。!

DESCRIPTION (provided by applicant): In recent years, cancer has surpassed heart disease as the leading cause of death among Americans who are younger than 85 years. In particular, breast cancer is the second leading cause of cancer-related deaths in the United States and often leads to secondary metastatic tumor sites in the bone, lungs, and liver. Tumor progression and metastasis involve two basic cellular processes: cell migration through interstitial tissues and cell division at the primary tumor and distal metastatic sites. During these processes, cells are subjected to complex three-dimensional environments that vary both biologically and physically. In this proposal, the overall objective is to evaluate how cell volume and polarity are regulated during migration and division when cells are subjected to varying degrees of physical confinement and/or matrix elasticity. We will use a combination of microfabricated devices, cell engineering techniques, and high-resolution phase contrast and laser scanning confocal timelapse microscopy to accomplish this objective. We hypothesize that the physical properties of the breast cancer cell microenvironment regulate cell volume and polarity during migration and the cell cycle. Two specific aims are proposed to address this hypothesis: (1) Elucidate the molecular mechanisms of cell migration and volume regulation in response to osmotic shock in confined microenvironments; and (2) Evaluate the effects of confinement and microenvironment elasticity on the spatial and temporal regulation of the cell cycle. The long-term goals of this project are to (1) contribute to our understanding of how cell volume and polarity are regulated during migration and division in confined microenvironments on a basic science level; (2) provide knowledge that could ultimately be used in the development of novel treatment strategies to control breast cancer cell proliferation and metastasis, (3) provide me with experimental and theoretical training in the field of cancer biophysics, which will be necessary for my future career as an independent researcher; and (4) contribute to my career development, through training on grant and manuscript writing, mentoring of graduate and undergraduate students, public speaking, and networking with future collaborators. Activities planned under the fellowship include original research (60% of time); manuscript preparation (10%); grant writing (10%); formal course work on Cancer Biology, Research Leadership, and Responsible Conduct of Research (5%); attendance at professional meetings (5%); participation in laboratory group meetings of our lab and collaborators (5%); mentoring Ph.D. and undergraduate students (2%); attendance at departmental seminars (2%); and participation in a postdoctoral journal club (1%). In completing the activities proposed under this fellowship, I will be prepared to begin an independent faculty career and will have the knowledge base and skill set to address biological problems relating to cancer using bioengineering strategies. !