Project 1: Effects of the Physical Microenvironment on Metabolism

项目摘要-项目1 三阴性乳腺癌(TNBC)的特征是肿瘤微环境的物理变化， 包括异常的多尺度结构和细胞外基质(ECM)的力学、扰动分布 可溶性因子，以及细胞组成和集体行为的群体水平异常(肿瘤 生态学)。此外，众所周知，肥胖会增加TNBC的风险并恶化其预后。然而， 微环境的这些物理变化与肿瘤代谢之间的功能联系 目前仍不清楚。这种理解上的差距在很大程度上可以归因于缺乏计算和实验 允许可靠地预测、概括和研究肿瘤和肥胖相关物理因素的模型 TNBC中的机制。通过整合生物材料、组织工程和微制造，我们的团队 在设计真实的文化微环境方面取得了重大进展，概括了生物学和 肿瘤的物理性质。此外，我们已经迭代地将这些平台与计算 生成新的可检验假说的模型。在这里，我们将利用这一专业知识来调查 微环境中的物理变化通过干扰细胞来调节恶性肿瘤的假说 新陈代谢。此外，我们将测试肥胖是否通过类似的生理机制导致肿瘤的发生。 和新陈代谢机制。我们将重点研究低氧诱导因子α(HIF1a)作为第一候选基因。 这些效应背后的分子途径，与其他候选者合作 项目2和项目3。这些假设基于我们的初步数据，并将在3个目标中进行测试 将以工程为中心的方法与转基因小鼠模型、PDX、患者衍生的有机化合物相结合 培养和药物测试。目标1将研究肿瘤和肥胖相关的物理机制 ECM诱导乳腺上皮细胞和间质细胞代谢重编程并确定 这些特性都是恶性的。目标2将定义HIF1a如何机械地将 肿瘤代谢、转移和药物反应的微环境。目标3将分析集体 复杂物理微环境中肿瘤的细胞动力学和基质细胞代谢重编程。 总的来说，这些研究将揭示肿瘤代谢重新编程的物理机制，并将这些联系起来 靶向分子机制的变化，从而为临床产生新的物理科学启发的见解 翻译。项目1大量使用组织微制造以及生物物理和代谢成像核心 并通过测试ECM物理特性在微泡生物发生中的作用来补充项目2和3 (项目2)，并通过评估肿瘤细胞的迁移和侵袭特性来响应定义的ECM物理 和运输特征(项目3)。

Project Summary – Project 1 Triple negative breast cancer (TNBC) is characterized by physical changes in the tumor microenvironment, including aberrant multiscale structure, and mechanics of the extracellular matrix (ECM), disturbed distributions of soluble factors, and population-level abnormalities in cellular composition and collective behavior (the tumor ecology). Additionally, obesity is known to increase the risk and worsen the prognosis for TNBC. However, the functional interconnections between these physical changes of the microenvironment and tumor metabolism remain unclear. This gap in understanding can be largely attributed to a lack of computational and experimental models that permit reliable prediction, recapitulation, and study of tumor and obesity-associated physical mechanisms in TNBC. By integrating biomaterials, tissue engineering, and microfabrication, our groups have made significant advances in the design of realistic culture microenvironments that recapitulate biological and physical properties of tumors. Furthermore, we have iteratively coupled these platforms with computational models to generate novel testable hypotheses. Here, we will capitalize on this expertise to investigate the overall hypothesis that physical changes in the microenvironment regulate malignancy by perturbing cellular metabolism. Furthermore, we will test whether obesity primes for tumorigenesis through similar physical and metabolic mechanisms. We will focus on hypoxia-inducible factor alpha (HIF1a) as a first candidate of the molecular pathways that underlie these effects, with other candidates pursued in collaboration with Projects 2 and 3. These hypotheses are based on our preliminary data and will be tested in 3 aims that will integrate engineering-centric approaches with transgenic mouse models, PDXs, patient-derived organoid cultures, and drug testing. Aim 1 will examine the physical mechanisms by which tumor and obesity-associated ECM induce metabolic reprogramming of mammary epithelial and stromal cells and define the consequences of these properties on malignancy. Aim 2 will define how HIF1a mechanistically links physical changes of the microenvironment with tumor metabolism, metastasis, and drug response. Aim 3 will analyze the collective cellular dynamics of tumor and stromal cell metabolic reprogramming in complex physical microenvironments. Collectively, these studies will reveal physical mechanisms in tumor metabolic reprogramming and link these changes to targetable molecular mechanisms thus generating new physical sciences-inspired insights for clinical translation. Project 1 heavily uses both the Tissue Microfabrication and Biophysics and Metabolic Imaging Cores and complements Projects 2 and 3 by testing the role of ECM physical properties in microvesicle biogenesis (Project 2) and by evaluating tumor cell migratory and invasive properties in response to defined ECM physical and transport characteristics (Project 3).