Engineered Microenvironments to model effect of size in tumor progression

工程微环境模拟肿瘤进展中大小的影响

基本信息

批准号：
8829249
负责人：
Shilpa Sant
金额：
$ 7.7万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829249
关键词：
Affect Apoptosis Apoptotic Area Basal Cell Basal Cell Cancer Basic Science Biological Breast Cancer Cell Breast Cancer Patient Cancer Etiology Cell Communication Cell-Cell Adhesion Cells Clinical Clinical Research Coupled Data E-Cadherin Engineering Epithelial Epithelium Event Exhibits Extracellular Matrix Generations Growth Health Hormonal Hydrogels Hypoxia Immunohistochemistry Intercellular Fluid Kinetics Link MCF10A cells MCF7 cell Mesenchymal Metabolic stress Modeling Molecular Molecular Profiling Morbidity - disease rate N-Cadherin Necrosis Neoplasm Metastasis Nodal Nutritional Outcome Oxygen Pathway interactions Patients Pattern Phenotype Preclinical Drug Evaluation Proliferating RNA Interference Radial Regulation Role Signal Transduction Snails Spatial Distribution Stress Stromal Cells Technology Tumor Cell Invasion Up-Regulation Vimentin Work in vivo inhibitor/antagonist insight interstitial malignant breast neoplasm monolayer mortality neoplastic cell novel novel strategies pressure receptor slug small molecule three-dimensional modeling transcription factor tumor tumor growth tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposal is to model the effect of tumor size and growth in promoting tumor progression. More specifically, the proposal aims to create a micro fabricated platform that will allow generation of uniform, size-controlled micro tumors in a high throughput manner and study size-dependent differences in tumor microenvironment, cell-cell interaction and transcription factors. Recently tumor microenvironment has been considered as an important player in tumorigenesis and progression leading to metastasis, a major cause of cancer-related mortality. Tumor microenvironment consists of tumor & stromal cells, extracellular matrix and non-cellular components that include hypoxia, interstitial pressure and metabolic stresses. Growing tumor exerts forces on the surrounding cells and epithelium creating radial and circumferential stress. Tumor growth also results in metabolic stress, hypoxia, necrosis, increased matrix stiffness and interstitial fluid pressure. Although tumor size has been considered as one of the important predictor of metastasis and patient survival, the mechanistic link between tumor size and the clinical outcome (metastasis, mortality) is not well understood. In breast cancer patients, this scenario is complicated by nodal and hormonal receptor status. This proposal aims 1) to develop three-dimensional (3D) micro fabricated platform to generate size-controlled micro tumors with controlled microenvironments using sub-type specific breast cancer cell lines and 2) to understand the effect of tumor size on microenvironment and delineate the mechanism by which tumor size promotes tumorigenesis and metastasis. Aim 1 will use micro fabrication technologies to pattern cells in non-adhesive hydrogel micro wells and generate size-controlled micro tumors of different sizes. Various sub-type specific cell lines (luminal, basal, triple negative etc.) will be used to investigate the size-dependent differences in their growth kinetics, hormonal status, cell-cell interaction and tumor microenvironment. In Aim 2, size-dependent transcriptional changes in micro tumors will be studied and this information will be used further to understand the mechanism behind tumor size-related tumor progression using RNA interference and small molecule inhibitors. The proposed approach is novel, easy and inexpensive and will allow fabricating 3D micro tumor models in a high throughput manner. Ability to control microenvironments in size-dependent manner will facilitate discovery of key signaling mechanisms involved in the regulation of morphological and transcriptional changes in tumor cells. This approach can potentially be used as a more relevant 3D drug screening platform to replace current 2D cell monolayers.

描述（由申请人提供）：该提案的目的是建模肿瘤大小和生长在促进肿瘤进展中的影响。更具体地说，该提案旨在建立一个微型制造的平台，该平台将以高通量方式产生均匀的，大小控制的微肿瘤，并在肿瘤微环境，细胞 - 细胞相互作用和转录因子中研究大小依赖性差异。最近，肿瘤微环境被认为是肿瘤发生和进展的重要参与者，导致转移是癌症相关死亡率的主要原因。肿瘤微环境由肿瘤和基质细胞，细胞外基质和非细胞成分组成，包括缺氧，间质压力和代谢应激。生长的肿瘤会在周围细胞上施加力，并在上皮上产生径向和圆周应激。肿瘤的生长还会导致代谢应激，缺氧，坏死，基质刚度增加和间质液压。尽管肿瘤的大小被认为是转移和患者存活的重要预测指标之一，但尚不清楚肿瘤大小与临床结果（转移，死亡率）之间的机械联系。在乳腺癌患者中，这种情况因淋巴结和荷尔蒙受体状态而复杂。该提议的目的是1）开发三维微型制造平台，以使用亚型特异性乳腺癌细胞系和2）来生成具有控制的微肿瘤，并使用受控的微环境和2）了解肿瘤大小对微环境的影响，并通过哪些肿瘤大小来促进肿瘤的机制，从而促进肿瘤和肿瘤。 AIM 1将使用微制造技术在非粘附水凝胶微孔井中进行模板细胞，并产生不同尺寸的大小控制的微肿瘤。各种亚型特异性细胞系（腔，基础，三重阴性等）将用于研究其生长动力学的尺寸依赖性差异，激素状态，细胞 - 细胞相互作用和肿瘤微环境。在AIM 2中，将研究微观肿瘤的大小依赖性转录变化，并将使用RNA干扰和小分子抑制剂来进一步使用该信息来了解与肿瘤大小相关的肿瘤进展的机制。所提出的方法是新颖，易于廉价的，可以以高通量方式制造3D微肿瘤模型。以尺寸依赖性方式控制微环境的能力将促进发现与肿瘤细胞形态学和转录变化调节有关的关键信号传导机制。这种方法可能被用作更相关的3D药物筛选平台，以替代当前的2D细胞单层。