Collaborative Research: Microengineered Tumor-Mimetic Collagen Landscapes to Test the Role of Prognostic Structural Cues on Cell Migration Through the Extracellular Matrix

合作研究：微工程模拟肿瘤胶原蛋白景观，以测试预后结构线索对细胞通过细胞外基质迁移的作用

• 批准号: 2150798
• 负责人: Vinay Abhyankar
• 金额: $ 34.07万
• 依托单位: Rochester Institute of Tech
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2150798&HistoricalAwards=false
• 关键词: Collaborative; Research; Microengineered; Tumor; Mimetic

The spread of cancer from the primary tumor to other locations in the body is called metastasis and is the leading cause of cancer-related deaths worldwide. The overarching goal of this collaborative research project is to determine how collagen properties that predict metastasis work together to guide cancer cell movement toward blood vessels. The project team will create a library of three-dimensional (3D) hydrogels containing different combinations of collagen properties and identify the properties that guide cancer cells through the tumor microenvironment. The new knowledge developed in this project will help researchers understand how different cancer cell sub-populations interact with their environment and identify possible targets for future anti-metastatic treatments. This project will also enhance the Rochester-area science, technology, engineering, and mathematics (STEM) pipeline by establishing a mentored summer program to support undergraduate student research at the Rochester Institute of Technology and University of Rochester campuses. Cancer metastasis is a process wherein tumor cells take on a migratory phenotype, invade the surrounding extracellular matrix (ECM), and infiltrate lymph and blood vessels. These circulating tumor cells can then seed secondary sites. The collagen-rich tumor ECM provides structural guidance cues that promote cell migration during the matrix invasion process. Using second harmonic generation (SHG) imaging of tumor collagen, it has been established that collagen fibers aligned perpendicular to the tumor-host interface are predictive of patient metastasis. The project team has recently shown that SHG forward/backward (F/B) imaging, sensitive to the spatial organization of collagen fibrils that comprise collagen fibers, is an independent predictor of metastasis in breast cancer patients. These fibril-level properties measured by SHG F/B are referred to as the collagen fiber internal structure (FIS). Although aligned collagen fibers and SHG F/B are both predictive of metastasis in human patients, it is unclear how these multiscale properties combine to influence the motility of tumor cells during matrix invasion. This project aims to test the hypothesis that FIS and fiber alignment properties combine in a synergistic and hierarchal manner to influence cell migration through the tumor ECM. The first objective is to use F/B measurements and fiber alignment properties from human tumor samples with known metastatic outcomes as a guide to microengineer 3D collagen scaffolds that replicate the multiscale tumor-mimetic collagen characteristics. The second objective is to systematically investigate how combinations of tumor-mimetic F/B and fiber alignment influence migratory characteristics of tumor cells with different metastatic potentials and then evaluate the role of Discoidin domain receptors as collagen FIS receptors. This project represents the first 3D microengineering efforts to combine and independently tune two clinically relevant structural cues, F/B and fiber alignment, and systematically evaluate their effects on tumor cell motility. This work could help advance metastatic prediction algorithms, support future therapeutic design efforts, and provide insight into the receptors that modulate cell-ECM interactions.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.

癌症从原发肿瘤扩散到身体其他部位称为转移，是全世界癌症相关死亡的主要原因。该合作研究项目的总体目标是确定预测转移的胶原蛋白特性如何共同作用，引导癌细胞向血管移动。该项目团队将创建一个包含不同胶原特性组合的三维 (3D) 水凝胶库，并确定引导癌细胞穿过肿瘤微环境的特性。该项目中开发的新知识将帮助研究人员了解不同的癌细胞亚群如何与其环境相互作用，并确定未来抗转移治疗的可能目标。该项目还将通过建立一个指导性暑期项目来支持罗彻斯特理工学院和罗彻斯特大学校园的本科生研究，从而增强罗彻斯特地区的科学、技术、工程和数学 (STEM) 渠道。癌症转移是肿瘤细胞呈现迁移表型、侵入周围细胞外基质（ECM）并浸润淋巴管和血管的过程。这些循环肿瘤细胞然后可以播种第二位点。富含胶原蛋白的肿瘤 ECM 提供结构引导线索，促进细胞在基质侵袭过程中迁移。使用肿瘤胶原的二次谐波发生（SHG）成像，已经确定垂直于肿瘤-宿主界面排列的胶原纤维可以预测患者的转移。该项目团队最近表明，SHG 前向/后向 (F/B) 成像对构成胶原纤维的胶原原纤维的空间组织敏感，是乳腺癌患者转移的独立预测因子。这些由 SHG F/B 测量的原纤维水平特性被称为胶原纤维内部结构 (FIS)。尽管对齐的胶原纤维和 SHG F/B 都可以预测人类患者的转移，但尚不清楚这些多尺度特性如何结合起来影响基质侵袭过程中肿瘤细胞的运动。该项目旨在测试 FIS 和纤维排列特性以协同和分层方式结合以影响细胞通过肿瘤 ECM 迁移的假设。第一个目标是利用具有已知转移结果的人类肿瘤样本的 F/B 测量和纤维排列特性作为微工程 3D 胶原蛋白支架的指南，复制多尺度肿瘤模拟胶原蛋白特征。第二个目标是系统地研究肿瘤模拟F/B和纤维排列的组合如何影响具有不同转移潜能的肿瘤细胞的迁移特征，然后评估Discoidin结构域受体作为胶原FIS受体的作用。该项目代表了第一个 3D 微工程努力，结合并独立调整两种临床相关的结构线索：F/B 和纤维排列，并系统地评估它们对肿瘤细胞运动的影响。这项工作可以帮助推进转移预测算法，支持未来的治疗设计工作，并提供对调节细胞-ECM相互作用的受体的深入了解。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力优势和更广泛的评估进行评估，被认为值得支持。影响审查标准。