Multicompartmentalized Microvascularized Tumor-on-a-Chip to Study Tumor-Stroma Interactions and Drug Resistance in Ovarian Cancer

IF 2.3 4区医学 Q3 BIOPHYSICS Cellular and molecular bioengineering Pub Date : 2024-09-14 DOI:10.1007/s12195-024-00817-y

Simona Plesselova, Kristin Calar, Hailey Axemaker, Emma Sahly, Amrita Bhagia, Jessica L. Faragher, Darci M. Fink, Pilar de la Puente

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Abstract

Introduction

The majority of ovarian cancer (OC) patients receiving standard of care chemotherapy develop chemoresistance within 5 years. The tumor microenvironment (TME) is a dynamic and influential player in disease progression and therapeutic response. However, there is a lack of models that allow us to elucidate the compartmentalized nature of TME in a controllable, yet physiologically relevant manner and its critical role in modulating drug resistance.

Methods

We developed a 3D microvascularized multiniche tumor-on-a-chip formed by five chambers (central cancer chamber, flanked by two lateral stromal chambers and two external circulation chambers) to recapitulate OC-TME compartmentalization and study its influence on drug resistance. Stromal chambers included endothelial cells alone or cocultured with normal fibroblasts or cancer-associated fibroblasts (CAF).

Results

The tumor-on-a-chip recapitulated spatial TME compartmentalization including vessel-like structure, stromal-mediated extracellular matrix (ECM) remodeling, generation of oxygen gradients, and delayed drug diffusion/penetration from the circulation chamber towards the cancer chamber. The cancer chamber mimicked metastasis-like migration and increased drug resistance to carboplatin/paclitaxel treatment in the presence of CAF when compared to normal fibroblasts. CAF-mediated drug resistance was rescued by ECM targeted therapy. Critically, these results demonstrate that cellular crosstalk recreation and spatial organization through compartmentalization are essential to determining the effect of the compartmentalized OC-TME on drug resistance.

Conclusions

Our results present a functionally characterized microvascularized multiniche tumor-on-a-chip able to recapitulate TME compartmentalization influencing drug resistance. This technology holds the potential to guide the design of more effective and targeted therapeutic strategies to overcome chemoresistance in OC.

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多室微血管化肿瘤芯片用于研究卵巢癌中肿瘤与基质之间的相互作用和耐药性

导言大多数接受标准化疗的卵巢癌（OC）患者会在 5 年内产生化疗耐药性。肿瘤微环境（TME）是影响疾病进展和治疗反应的动态因素。我们开发了一种三维微血管化多微切肿瘤芯片，由五个腔室（中央癌症腔室、两侧基质腔室和两个外循环腔室）组成，以再现肿瘤微环境的分区，并研究其对耐药性的影响。基质室包括单独的内皮细胞或与正常成纤维细胞或癌症相关成纤维细胞（CAF）共培养的内皮细胞。结果片上肿瘤再现了TME的空间分区，包括血管样结构、基质介导的细胞外基质（ECM）重塑、氧梯度的产生以及药物从循环室向癌症室的延迟扩散/渗透。与正常成纤维细胞相比，在有 CAF 存在的情况下，癌症室模拟了类似转移的迁移，并增加了对卡铂/紫杉醇治疗的耐药性。ECM 靶向疗法可挽救 CAF 介导的耐药性。重要的是，这些结果表明，细胞串扰再现和空间组织分区对于确定分区 OC-TME 对耐药性的影响至关重要。这项技术有望指导设计更有效、更有针对性的治疗策略，以克服 OC 的化疗耐药性。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.