CAREER: Cancer-associated secondary lymphedema on-chip

淋巴水肿是由淋巴引流不良引起的肿胀。在美国，乳腺癌患者手臂水肿的发生率很高。该CAREER项目的目标是了解乳腺癌中淋巴结构和功能的调节，并通过建立一个专门研究乳腺癌淋巴引流的独特细胞培养平台，发现治疗与乳腺癌相关的水肿的新方法。该项目可能有助于开发新疗法，使数百万水肿患者受益，并提高美国的健康结果。涉及康奈尔大学和当地高中学生的教育计划与研究目标保持一致。一个代表性不足的本科生多元化群体的招聘和培训将通过康奈尔大学工程学习计划和Prefreshman暑期项目进行。与新视野工程和康奈尔大学科学技术入门计划的合作将进一步吸引弱势高中学生参与与淋巴研究相关的实践活动。此外，该项目的教育计划将创建在线课程，以提高对淋巴疾病的科学认识。淋巴水肿的特点是由于淋巴引流受损而肿胀，全球有超过1.5亿患者受到影响。尽管其流行，但没有FDA批准的治疗，常用的保守疗法主要提供姑息性缓解。这个CAREER项目旨在研究水肿的机制，确定潜在的治疗靶点和治疗策略。虽然遗传缺陷可导致原发性水肿，但继发性水肿，特别是乳腺癌相关的继发性水肿更为常见。然而，目前对乳腺癌相关继发性水肿的机制理解有限。缺乏正常和受损淋巴引流的实验模型一直是一个重大障碍。主要研究者通过微流体培养模型解决了这一挑战，该模型具有模拟关键淋巴内皮细胞-细胞连接的工程淋巴管。这些连接对于促进淋巴引流至关重要，并允许研究它们在乳腺癌等疾病中如何受到影响。该项目通过创建复制乳腺肿瘤淋巴微环境的组织工程共培养模型来扩展这项工作。这些模型涉及在活体外的明确定义的三维空间中培养多个乳腺肿瘤细胞和淋巴细胞。一项初步研究显示，三阴性乳腺癌细胞影响淋巴结构和功能，导致引流受损。该研究分为两个具体目标：目标1侧重于了解乳腺癌淋巴结结构和引流功能的调节，目标2集中于乳腺癌相关继发性水肿的治疗。结合教育外展，这个CAREER项目将有助于开发新的治疗方法，在美国的水肿患者，并将提高淋巴疾病和微生理系统的科学意识。这个奖项反映了NSF的法定使命，并已被认为是值得通过评估使用基金会的智力价值和更广泛的影响审查标准的支持。

Lymphedema is swelling caused by poor lymphatic drainage. In the US, breast cancer patients show a high incidence of lymphedema in their arms. The goals of this CAREER project are to comprehend the regulation of the lymphatic structure and function in breast cancer and to discover novel approaches to treating lymphedema linked to breast cancer through the establishment of a unique cell culture platform dedicated to studying lymphatic drainage in breast cancer. This project may contribute to the development of new therapies benefitting millions of lymphedema patients and enhancing health outcomes in the US. Educational initiatives involving Cornell and local high school students are aligned with the research goals. The recruitment and training of a diverse group of underrepresented undergraduate students will be carried out through Cornell Engineering Learning Initiatives and the Prefreshman Summer Program. Collaborations with New Visions Engineering and the Cornell Science and Technology Entry Program will further engage disadvantaged high school students in hands-on activities related to lymphatic research. Additionally, the project's educational program will create online courses to raise scientific awareness of lymphatic diseases.Lymphedema, characterized by swelling due to impaired lymphatic drainage, affects over 150 million patients worldwide. Despite its prevalence, there is no FDA-approved treatment, and commonly used conservative therapies provide primarily palliative relief. This CAREER project seeks to investigate the mechanisms of lymphedema, identifying potential therapeutic targets and treatment strategies. While genetic defects can cause primary lymphedema, secondary lymphedema, particularly breast cancer-associated secondary lymphedema, is more common. However, the mechanistic understanding of breast cancer-associated secondary lymphedema is currently limited. The lack of experimental models for normal and impaired lymphatic drainage has been a significant obstacle. The principal investigator addresses this challenge with a microfluidic culture model featuring an engineered lymphatic vessel that mimics key lymphatic endothelial cell-cell junctions. These junctions are crucial for facilitating lymphatic drainage and allow for the study of how they are affected in conditions such as breast cancer. The project extends this work by creating tissue-engineered co-culture models replicating the breast tumor lymphatic microenvironment. These models involve culturing multiple breast tumor cells and lymphatic cells in a well-defined three-dimensional space outside living organisms. A pilot study revealed that triple-negative breast cancer cells impact lymphatic structure and function, leading to impaired drainage. The research is organized into two specific aims: Aim 1 focuses on understanding the regulation of lymphatic junction structure and drainage function in breast cancer and Aim 2 centers on the treatment of breast cancer-associated secondary lymphedema. In conjunction with educational outreach, this CAREER project will contribute to the development of new therapies for lymphedema patients in the US and will enhance scientific awareness of lymphatic disease and microphysiological systems.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.