CAREER: Probing the Physiochemical Regulators of Tumor Stroma Interactions Using Microfluidic Biomimicry

职业：利用微流仿生学探索肿瘤基质相互作用的理化调节因子

• 批准号: 1752106
• 负责人: Jonathan Song
• 金额: $ 54.64万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1752106&HistoricalAwards=false
• 关键词: CAREER; Probing; Physiochemical; Regulators; Tumor

Solid tumors are composed of cancer cells and the tissue surrounding the cancer cells, called the stroma. The stroma, which includes vascular cells, inflammatory/immune cells, and connective tissues, has emerged as an important determinant of tumor behavior. Therefore, a critical need exists for identifying the tumor promoting properties of the stroma. This project will use micro-scale engineering technology to construct a microfluidic model of the tumor stroma. The model will include the cellular, extracellular matrix, and biomolecular constituents of the tumor stroma. This novel model platform will be used to precisely examine the mechanisms by which the cellular components of the tumor stroma promote cancer progression. The successful outcome of this research will remove technical barriers to studying the tumor microenvironment, and it will provide a deeper understanding of the role of tumor stroma in cancer. The research program will be closely coupled with the PI's educational mission of increasing the pipeline of engineering students contributing to interdisciplinary cancer research by promoting awareness of the opportunities for engineering students towards this exciting academic career path at the interface of engineering and cancer. This project will support this vision through a combined education and outreach plan that is organized as a series of initiatives that start at the middle and high school level and proceed to the senior undergraduate level while also engaging the local community. Collectively, the outreach efforts will leverage the strong appeal that cancer research has as a top priority societal need with an emphasis on attracting, retaining, and promoting resilience of female students, who are underrepresented in engineering.This project seeks to advance understanding of the physiochemical mechanisms by which stromal fibroblasts reprogram the tumor microenvironment (TME) through autocrine, paracrine, and pericellular matrix communication, with a particular focus on stroma activation that is controlled by different isoforms of the chemokine CXCL12 (or SDF-1), a signaling molecule that drives cancer metastasis in more than 23 different cancers. An innovative approach, combining a) microscale engineering technologies that precisely model the stromal cell-endothelial cell interactions within the TME, b) quantitative microstructural analysis of the ECM, and c) molecular imaging probes that detect changes in the local biomolecular microenvironment, will be used to systematically investigate, with high degrees of fidelity and facile experimental control, the pathogenesis of an activated stroma microenvironment. The research aims are designed to test two hypotheses: 1)To quantify the effects on fibroblast activation that are CXCL12 isoform specific, using the microfluidic tumor stroma model combined with quantitative assessment of ECM remodeling, to test the hypothesis that alterations to ECM content and microstructure by stromal fibroblasts are important determinants in distinguishing the potencies of different CXCL12 isoforms and 2) To distinguish specific isoforms of CXCL12 on their angiogenesis and vascular permeability promoting properties, using the PI's angiogenesis-on-a-chip (AoC) platform, to test the hypothesis that the potency of different CXCL12 isoforms on angiogenesis and vascular permeability is determined by changes to the ECM content and microstructure. The studies will be performed in the context of breast cancer, and mammary fibroblasts that selectively secrete three distinct CXCL12-isoforms will be used as the model for stromal fibroblasts. Completion of these aims will result in a significant advancement of our quantitative understanding of reactive stroma responses mediated by CXCL12 regulatory circuits.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.

实体瘤由癌细胞和癌细胞周围的组织组成，称为基质。间质包括血管细胞、炎症/免疫细胞和结缔组织，已成为肿瘤行为的重要决定因素。因此，迫切需要鉴定基质的促肿瘤性质。本计画将利用微尺度工程技术建构肿瘤间质的微流体模型。 该模型将包括肿瘤间质的细胞、细胞外基质和生物分子成分。 这种新的模型平台将用于精确地研究肿瘤基质的细胞成分促进癌症进展的机制。 这项研究的成功结果将消除研究肿瘤微环境的技术障碍，并将更深入地了解肿瘤基质在癌症中的作用。 该研究计划将与PI的教育使命紧密结合，即通过提高对工程专业学生在工程和癌症界面上走向这一令人兴奋的学术职业道路的机会的认识，增加工程专业学生对跨学科癌症研究的贡献。该项目将通过一个综合教育和推广计划来支持这一愿景，该计划是作为一系列举措组织的，从初中和高中开始，一直到高年级本科生，同时也让当地社区参与进来。总的来说，外展工作将利用癌症研究作为最优先的社会需求的强烈吸引力，重点是吸引，保留和促进女性学生的恢复能力，这些学生在工程领域代表性不足。该项目旨在促进对基质成纤维细胞通过自分泌，旁分泌和细胞周基质通讯重新编程肿瘤微环境（TME）的生理化学机制的理解，特别关注由趋化因子CXCL 12（或SDF-1）的不同亚型控制的基质激活，CXCL 12是一种驱动超过23种不同癌症转移的信号分子。 一种创新的方法，结合了a）精确模拟TME内基质细胞-内皮细胞相互作用的微尺度工程技术，B）ECM的定量显微结构分析，和c）检测局部生物分子微环境变化的分子成像探针，将用于系统地研究，具有高度的保真度和容易的实验控制，活化的基质微环境的发病机制。本研究旨在验证两个假设：1）使用微流体肿瘤基质模型结合ECM重塑的定量评估，定量对CXCL 12同种型特异性的成纤维细胞活化的影响，检验基质成纤维细胞对ECM含量和微观结构的改变是区分不同CXCL 12同种型效力的重要决定因素的假设，以及2）为了区分CXCL 12的特定同种型在其血管生成和血管渗透性促进特性方面的差异，使用PI的芯片上血管生成（AoC）平台，以测试不同CXCL 12同种型对血管生成和血管渗透性的效力由ECM含量和微观结构的变化决定的假设。 这些研究将在乳腺癌的背景下进行，选择性分泌三种不同CXCL 12亚型的乳腺成纤维细胞将用作基质成纤维细胞的模型。 这些目标的完成将导致我们对CXCL 12调节电路介导的反应性基质反应的定量理解的显著进步。该奖项反映了NSF的法定使命，并被认为值得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来支持。

项目成果

Electromagnetic fields alter the motility of metastatic breast cancer cells

• DOI: 10.1038/s42003-019-0550-z
• 发表时间: 2019-08-08
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Garg, Ayush Arpit;Jones, Travis H.;Song, Jonathan W.
• 通讯作者: Song, Jonathan W.

Extracellular Matrix-Derived Biophysical Cues Mediate Interstitial Flow-Induced Sprouting Angiogenesis

• DOI: 10.1021/acsami.2c15180
• 发表时间: 2023-03-14
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Chang，Chia-Wen;Shih，Hsiu-Chen;Song，Jonathan W.
• 通讯作者: Song，Jonathan W.

Distinguishing Specific CXCL12 Isoforms on Their Angiogenesis and Vascular Permeability Promoting Properties

• DOI: 10.1002/adhm.201901399
• 发表时间: 2020-01-15
• 期刊: ADVANCED HEALTHCARE MATERIALS
• 影响因子: 10
• 作者: Chang, Chia-Wen;Seibel, Alex J.;Song, Jonathan W.
• 通讯作者: Song, Jonathan W.

Application of 3-D Microfluidic Models for Studying Mass Transport Properties of the Tumor Interstitial Matrix

• DOI: 10.3389/fbioe.2019.00006
• 发表时间: 2019-01-23
• 期刊: FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
• 影响因子: 5.7
• 作者: Avendano, Alex;Cortes-Medina, Marcos;Song, Jonathan W.
• 通讯作者: Song, Jonathan W.

In utero estrogenic endocrine disruption alters the stroma to increase extracellular matrix density and mammary gland stiffness

子宫内雌激素内分泌干扰改变基质，增加细胞外基质密度和乳腺硬度

• DOI: 10.1186/s13058-020-01275-w
• 发表时间: 2020
• 期刊: Breast Cancer Research
• 影响因子: 7.4
• 作者: Wormsbaecher, Clarissa;Hindman, Andrea R.;Avendano, Alex;Cortes-Medina, Marcos;Jones, Caitlin E.;Bushman, Andrew;Onua, Lotanna;Kovalchin, Claire E.;Murphy, Alina R.;Helber, Hannah L.
• 通讯作者: Helber, Hannah L.