CAREER: Engineering biomimetic environments to elucidate mechanisms of dormancy in brain metastatic breast cancer cells

职业：设计仿生环境以阐明脑转移性乳腺癌细胞的休眠机制

基本信息

批准号：
1749837
负责人：
Shreyas Rao
金额：
$ 51.49万
依托单位：
University of Alabama Tuscaloosa
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1749837&HistoricalAwards=false
关键词：
CAREER Engineering biomimetic environments elucidate

项目摘要

A majority of breast cancer-related deaths worldwide occur as a result of the cancer spreading to one or more organs, often described as becoming "metastatic." Accumulating evidence suggests that cancer cells can reside in vital organs (e.g., brain) in a sleep mode (dormant) for extended periods of time and could reawaken at a later stage resulting in disease relapse and often death. However, the mechanisms by which metastatic breast cancer cells in the brain stay dormant and later become activated are not well understood, making it difficult to develop new therapeutic strategies. A few experimental models have been devised for studying dormancy in metastatic breast cancer cells; however, experimental model systems to study dormancy in brain metastatic breast cancer cells outside of a living organism (in vitro) are not available. This project focuses on developing an engineered biomimetic three dimensional in vitro experimental model of dormancy to study how biophysical, biochemical, and cellular signals of the brain tissue microenvironment regulate dormancy in brain metastatic breast cancer cells and define the associated molecular mechanisms. The technologies developed and insights gained could be broadly applied to fundamental investigations of neural development, tissue regeneration, and stem cell engineering as stem cells typically stay in a dormant state until activated to promote tissue repair, and could be used to study dormancy in other types of brain metastatic cancers. The education and outreach plans are well integrated with research and include: providing educational sessions in high schools and in a "Scientist for a Day" program, initiating a four-day mentored research experience for students and teachers from Alabama's economically challenged Black Belt region, providing research experiences for undergraduate students and enhancing undergraduate and graduate education by developing a course in cancer bioengineering and tailoring existing coursework to incorporate problems with biological relevance. These activities are designed with the goal of motivating pursuit of STEM careers for students from socially and economically challenged backgrounds, women, and minority students.The project focuses on developing an in vitro model to test the hypothesis that biophysical, biochemical and cellular cues in the brain microenvironment regulate the dormancy of breast cancer cells that have metastasized to the brain. Three dimensional (3D) tissue-mimetic hydrogel scaffolds using hyaluronic acid will be engineered to replicate biochemical composition, mechanics and cellular components of the brain. The scaffolds created will provide controllable systems to investigate microenvironment-tumor cell interactions, to study the mechanisms controlling dormancy and to test if the dormant phenotype observed in BCBM cells is reversible by modulating the scaffold environment. The Research Plan is organized under 4 specific aims: 1) Investigate the influence of mechanical cues (stiffness and mechanotransduction pathways) in regulating tumor dormancy in vitro; 2) Investigate the influence of biochemical cues (biomolecules found in the brain tumor extracellular matrix) in regulating tumor dormancy in vitro; 3) Investigate the influence of cellular cues (astrocytes) in regulating tumor dormancy in vitro and 4) Examine known signaling pathways (e.g., p38 and TGF-Beta) regulating dormancy in the biomimetic environment in vitro and identify additional pathways using a systems biology approach (proteomics and genomics), i.e., to elucidate the mechanisms governing dormancy in the engineered biomimetic scaffold, linking microenvironmental factors to the ultimate cellular phenotype: "dormant" or "proliferative."This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

全世界大多数与乳腺癌相关的死亡发生在癌症上，这是由于癌症扩散到一个或多个器官，通常被描述为“转移性”。积累的证据表明，癌细胞可以在睡眠模式（休眠）长时间驻留在重要器官（例如大脑）中，并且可以在以后的阶段重新捕获，从而导致疾病复发并经常死亡。但是，脑中转移性乳腺癌细胞保持休眠状态并随后被激活的机制尚不清楚，因此很难制定新的治疗策略。已经设计了一些用于研究转移性乳腺癌细胞休眠的实验模型。但是，研究生物体外（体外）外脑转移性乳腺癌细胞休眠的实验模型系统（体外）。该项目着重于开发一种工程的仿生三维体外体外实验模型，以研究脑组织微环境的生物物理，生化和细胞信号如何调节脑转移性乳腺癌细胞的休眠状态并定义相关的分子机制。开发的技术和获得的见解可以广泛应用于神经发育，组织再生和干细胞工程的基本研究，因为干细胞通常保持在休眠状态，直到被激活以促进组织修复，并可用于研究其他类型的脑转移性癌症的休眠状态。教育和宣传计划与研究充分融合，包括：在高中和“一日科学家”计划中提供教育课程，为阿拉巴马州经济挑战的黑带地区的学生和老师提供为期四天的指导研究经验，为在本科生中的研究和培养课程中的研究和培养型癌症和研究生型和范围的努力和统治型癌症和努力，为癌症的研究提供了研究，并为癌症提供了研究。这些活动的设计旨在激励从社会和经济挑战背景，妇女和少数群体的学生追求STEM职业。该项目着重于开发一种体外模型，以检验以下假设，即脑微环境中生物物理，生化和细胞线索的假设调节乳腺癌细胞的乳腺癌细胞的结束，这些乳腺癌细胞具有转化为脑部的乳腺癌细胞。使用透明质酸将设计三维（3D）组织模拟水凝胶支架，以复制大脑的生化组成，力学和细胞成分。创建的脚手架将提供可控的系统，以研究微环境肿瘤细胞相互作用，研究控制休眠状态的机制，并测试通过调节脚手架环境，可逆转在BCBM细胞中观察到的休眠表型。该研究计划是根据4个特定目的组织的：1）研究机械提示（刚度和机械转导途径）对调节体外肿瘤休眠的影响； 2）研究生化线索（在脑肿瘤外基质中发现的生物分子）在体外调节肿瘤休眠的影响； 3）研究细胞提示（星形胶质细胞）在体外调节肿瘤休眠的影响和4）检查已知的信号传导途径（例如p38和TGF-β）调节体外生物模拟环境中休眠的已知信号传导途径（例如p38和TGF-beta），并使用系统的生物学方法（蛋白质组学）来识别其他途径，并确定其他途径。脚手架，将微环境因素与最终的细胞表型联系起来：“休眠”或“增殖”。该奖项反映了NSF的法定任务，并被认为是通过基金会的智力优点和更广泛影响的评估来评估值得支持的。