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

该项目将研究乳腺癌细胞如何对局部肿瘤环境做出反应并侵入邻近组织。在乳腺肿瘤中，生化信号导致癌细胞侵入附近的健康组织。产生这些信号的细胞被称为成纤维细胞。成纤维细胞也使肿瘤变硬。众所周知，乳房肿瘤较硬的患者通常预后较差。过去对这些肿瘤的研究分别研究了生化信号和机械刚度。因此，这两个过程对癌细胞侵袭的综合影响尚不清楚。该项目的目标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房肿瘤模型和成像生物传感器。这项工作将测量细胞信号和机械力。这项研究的发现可能最终有助于开发减少转移的新治疗策略。通过一系列教育活动，该项目将扩大少数族裔在STEM领域的参与。因此，该项目还将为STEM领域的下一代领导者提供新的培训和研究机会，从而造福社会。癌相关成纤维细胞（CAFs）重塑细胞外基质（ECM）并分泌促进多种恶性肿瘤侵袭和转移的信号分子。虽然这些事件通常被认为是独立的实体，但它们在改变肿瘤环境方面的综合作用尚不清楚。研究人员假设，癌细胞建立了对机械环境的记忆，这种记忆塑造了对来自CAFs的生化信号的反应，以及癌细胞侵入邻近组织的能力。以乳腺癌为重点，该项目将开发和应用用于单细胞和亚细胞力测量和信号输出的定量成像生物传感器，以及用于表型和整个肿瘤水平测量的组织工程乳腺肿瘤模型。研究小组将定量地(i)确定基质收缩和caf旁分泌信号传导之间的相互作用如何促进癌细胞的侵袭性间充质表型并改变其对靶向治疗的反应；（ii）确定基质组成和刚度对核结构和色凝的影响，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。

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.