Collaborative Research: Integrated Analysis of Mechanical and Biochemical Effects in Breast Tumor Microenvironment

合作研究：乳腺肿瘤微环境中机械和生化效应的综合分析

• 批准号: 2140091
• 负责人: Gary Luker
• 金额: $ 29.98万
• 依托单位: Regents of the University of Michigan - Ann Arbor
• 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: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2140091&HistoricalAwards=false
• 关键词: Collaborative; Research; Integrated; Analysis; Mechanical

This project will study how breast cancer cells respond to the local tumor environment and invade adjacent tissue. In breast tumors, biochemical signals lead to cancer cells invading nearby healthy tissue. The cells that produce these signals are called fibroblasts. Fibroblast cells also make tumors stiffer. It is known that patients with stiffer breast tumors typically have poorer outcomes. Past research on these tumors has studied biochemical signaling and mechanical stiffness separately. As such, the combined effects of these two processes on cancer cell invasion remain unknown. The goal of the project is to understand how biochemical and mechanical inputs together enable invasion of healthy tissue. The interdisciplinary research team will use state-of-the-art bioengineered breast tumor models and imaging biosensors. The work will measure both cell signaling and mechanical forces. Findings from this research may eventually help develop new treatment strategies that reduce metastasis. Through a range of educational activities, this project will broaden participation of underrepresented minorities in STEM fields. Therefore, this project will also benefit society by providing new training and research opportunities for the next generation of leaders in STEM fields. Carcinoma-associated fibroblasts (CAFs) remodel the extracellular matrix (ECM) and secrete signaling molecules that promote invasion and metastasis in multiple malignancies. While these events are commonly considered as independent entities, their integrated effects in altering the tumor environments are unknown. The investigators hypothesize that cancer cells establish a memory of mechanical environments that shapes responses to biochemical signals from CAFs and the ability of cancer cells to invade into adjacent tissue. Focusing on breast cancer, this project will develop and apply quantitative imaging biosensors for single-cell and subcellular force measurements and signaling outputs, and a tissue-engineered breast tumor model for phenotypic and whole tumor-level measurements. The research team will quantitatively (i) determine how the interplay between matrix contraction and paracrine signaling of CAFs promotes an invasive mesenchymal phenotype in cancer cells and alters their responses to targeted therapies; and (ii) establish effects of matrix composition and stiffness on nuclear architecture and chromatic condensation that enable cancer cells to retain a signaling memory of their mechanical environment.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.

该项目将研究乳腺癌细胞如何应对局部肿瘤环境并侵入相邻组织。在乳腺肿瘤中，生化信号导致癌细胞入侵附近的健康组织。 产生这些信号的细胞称为成纤维细胞。 成纤维细胞还使肿瘤更硬。众所周知，患有较硬的乳腺肿瘤的患者的预后较差。过去对这些肿瘤的研究已分别研究了生化信号传导和机械刚度。 因此，这两个过程对癌细胞浸润的综合作用尚不清楚。该项目的目的是了解生化和机械输入如何共同入侵健康组织。跨学科研究团队将使用最先进的生物工程乳腺肿瘤模型和成像生物传感器。 该工作将测量细胞信号传导和机械力。这项研究的结果最终可能有助于制定新的治疗策略，以减少转移。通过一系列教育活动，该项目将扩大代表性不足的少数民族在STEM领域的参与。因此，该项目还将通过为STEM领域的下一代领导者提供新的培训和研究机会来使社会受益。癌相关的成纤维细胞（CAFS）重塑细胞外基质（ECM）和分泌信号分子，可促进多种恶性肿瘤中侵袭和转移。尽管这些事件通常被视为独立实体，但它们在改变肿瘤环境中的综合效应尚不清楚。研究人员假设癌细胞建立了机械环境的记忆，该机械环境塑造了对CAFS的生化信号的反应以及癌细胞侵入相邻组织的能力。该项目的重点是乳腺癌，将开发并应用定量成像生物传感器，用于单细胞和亚细胞力测量和信号输出，以及组织工程设计的乳腺肿瘤模型，用于表型和整个肿瘤水平的测量。研究团队将定量（i）确定基质收缩与CAF的旁分泌信号之间的相互作用如何促进癌细胞中的侵入性间充质表型，并改变其对靶向疗法的反应； （ii）建立基质组成和刚度对核结构和色素凝结的影响，使癌细胞能够保留其机械环境的信号记忆。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和更广泛影响的审查标准通过评估来通过评估来支持的。