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，并侵袭邻近组织。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被称为成纤维细胞。成纤维细胞也会使肿瘤变得更硬。众所周知，乳腺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僵硬。因此，这两个过程对癌细胞侵袭的联合影响尚不清楚。该项目的目标是了解生化和机械输入如何一起使健康组织入侵。这个跨学科的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。这项工作将同时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，该项目将扩大代表不足的少数群体在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。肿瘤相关成纤维细胞(CAF)重塑细胞外基质(ECM)并分泌信号分子，促进多种恶性肿瘤的侵袭和转移。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影响尚不清楚。研究人员假设，癌细胞建立了对机械环境的记忆，这种记忆形成了对CAF生物化学信号的反应，以及癌细胞侵入邻近组织的能力。该项目将以乳腺癌为重点，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。研究团队将定量(I)确定CAF的基质收缩和旁分泌信号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；以及(Ii)建立基质组成和硬度对核结构和染色凝结的影响，使癌细胞能够保持对其机械环境的信号记忆。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.