CAREER: In Vitro Model Approaches Leveraging Quantitative Cancer Cell Properties as Determinants of Metastatic Potential

当肿瘤细胞脱离原来的肿瘤并移动或扩散到身体的其他部位时，就会发生癌症转移。就乳腺癌而言，大多数患者的死亡是由于转移到身体的其他部位，包括骨骼、肺和大脑。因此，早期和可靠地识别有可能成为转移细胞的细胞是很重要的。该CAREER提案旨在开发基于测量癌细胞定量特性的新策略，以更好地了解导致转移性癌症的原因以及转移性细胞与非转移性细胞区分的特定特征。拟议的工作整合了一项全面的教育计划，以实现增加代表性不足的少数民族参与生物医学工程的主要目标。该计划将通过研究指导和规划来培养对生物医学工程和研究的认识和兴趣，为学生提供生物医学职业道路的早期认识。此外，还将为各级开展教育外展活动，包括针对K-12和大学生的倡议，以及以社区为重点的健康和外展日。研究者的长期研究目标是开发策略和工具，以帮助更好地了解肿瘤微环境在癌症转移中的作用，从而改善转移性癌症患者的健康结果。为了对临床结果做出显著的积极贡献，首先有必要更好地了解癌细胞过程和肿瘤微环境中特定因素对癌细胞行为的影响，以便更早、更可靠地识别转移细胞。为了实现这一目标，本CAREER项目主要侧重于了解癌细胞转移的影响因素，特别关注细胞外基质（ECM）和脂肪分泌因子的作用。本CAREER提案的研究目的旨在验证乳腺癌细胞具有与阻抗、形态和基因/蛋白表达相关的固有表型特征，这些特征区分了转移细胞和非转移细胞。具体来说，这项工作的目的将是：1)评估不同类型乳腺癌细胞的阻抗谱，以识别特定细胞类型的不同阻抗特征；2)通过量化细胞形态的变化，确定与乳腺癌细胞转移相关的形态学特征；3)利用阻抗和形态学分析评估细胞因子对乳腺癌转移的影响。定量体外建模方法将被应用于获得定量数据，用于描述转移癌细胞的特定特征。确定转移性癌细胞的特异性特征将对推进未来的癌症研究和临床应用产生深远的影响。整合到这项工作中的是一个全面的教育计划，旨在满足PI的长期教育目标，即提高科学、技术、工程和数学（STEM）的意识，并使代表性不足的少数民族参与生物医学研究和职业道路。具体的教育目标是：1)通过教育和社区外展，从K-12到灰色人群，跨代促进STEM和健康意识；2)支持各级跨学科研究指导和规划，以增加少数族裔学生攻读生物医学工程研究生学位的人数。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Cancer metastasis occurs when tumor cells break away from the original tumor and move, or spread to other parts of the body. In the case of breast cancer, the majority of patient deaths are as a result of metastasis to other parts of the body, including bones, lung, and brain. Thus, it is important to identify cells that have the potential to be metastatic cells early and reliably. This CAREER proposal aims to develop novel strategies based on measuring quantitative properties of cancer cells to better understand what contributes to metastatic cancer and what specific signature metastatic cells have that distinguishes them from non-metastatic cells. The proposed work integrates a comprehensive education plan for meeting the primary objective of increasing the participation of underrepresented minorities in biomedical engineering. This plan will foster awareness and interest in biomedical engineering and research through research mentoring and programming developed to provide early awareness of biomedical career paths for students. In addition, educational outreach events for all levels will be implemented, including initiatives for K-12 and college students, as well as community-focused Health & Outreach Days. The investigator's long-term research goal is to develop strategies and tools that will help to better understand the role of the tumor microenvironment in cancer metastasis, which will lead to improved health outcomes for patients with metastatic cancer. To make significant positive contributions to clinical outcomes, it is necessary to first have a better fundamental understanding of cancer cell processes and the effects of specific factors from the tumor microenvironment on cancer cell behavior to identify metastatic cells earlier and more reliably. Towards this goal, this CAREER project primarily focuses on understanding contributors to cancer cell metastasis, with a specific focus on the role of the extracellular matrix (ECM) and adipose-secreted factors. The research objectives of this CAREER proposal are aimed at testing the hypothesis that breast cancer cells have inherent phenotypical characteristics associated with impedance, morphology, and gene/protein expression, which distinguish metastatic cells from non-metastatic cells. Specifically, the aims of this work will: 1) assess the impedance profiles for breast cancer cells of varying type to identify distinct impedance signatures for specific cell types; 2) identify morphological features associated with breast cancer cell metastasis by quantifying changes in cell shape; and 3) assess the effects of cytokines on breast cancer metastasis using impedance and morphology-based analyses. Quantitative in vitro modeling approaches will be applied to obtain quantitative data that will be used to delineate the specific signature of metastatic cancer cells. Determination of specific characteristics useful for identifying metastatic cancer cells will have far-reaching impact for advancing future cancer research and clinical applications. Integrated into this work is a comprehensive educational plan towards meeting the PI’s long-term educational goal of increasing science, technology, engineering, and mathematics (STEM) awareness and participation of underrepresented minorities in biomedical research and career paths. Specific educational objectives are to: 1) promote STEM and health awareness through educational and community outreach across generations, from K-12 through gray populations; and 2) support cross-disciplinary research mentorship and programming at all levels to increase the number of underrepresented minority students pursuing graduate degrees in biomedical engineering.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.