Doffe Flora, Bonini Fabien, Lakis Emile, Terry Stéphane, Chouaib Salem, Savagner Pierre
INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculty of Medicine, University Paris-Saclay, 94805 Villejuif, France.
Department of Pathology and Immunology, Faculty of Medicine, University Geneva, 1205 Geneva, Switzerland.
Cancers (Basel). 2022 Jul 22;14(15):3559. doi: 10.3390/cancers14153559.
The recent trend in 3D cell modeling has fostered the emergence of a wide range of models, addressing very distinct goals ranging from the fundamental exploration of cell-cell interactions to preclinical assays for personalized medicine. It is clear that no single model will recapitulate the complexity and dynamics of in vivo situations. The key is to define the critical points, achieve a specific goal and design a model where they can be validated. In this report, we focused on cancer progression. We describe our model which is designed to emulate breast carcinoma progression during the invasive phase. We chose to provide topological clues to the target cells by growing them on microsupports, favoring a polarized epithelial organization before they are embedded in a 3D matrix. We then watched for cell organization and differentiation for these models, adding stroma cells then immune cells to follow and quantify cell responses to drug treatment, including quantifying cell death and viability, as well as morphogenic and invasive properties. We used model cell lines including Comma Dβ, MCF7 and MCF10A mammary epithelial cells as well as primary breast cancer cells from patient-derived xenografts (PDX). We found that fibroblasts impacted cell response to Docetaxel and Palbociclib. We also found that NK92 immune cells could target breast cancer cells within the 3D configuration, providing quantitative monitoring of cell cytotoxicity. We also tested several sources for the extracellular matrix and selected a hyaluronan-based matrix as a promising alternative to mouse tumor basement membrane extracts for primary human cancer cells. Overall, we validated a new 3D model designed for breast cancer for preclinical use in personalized medicine.
3D细胞建模的最新趋势催生了各种各样的模型，这些模型旨在实现从细胞间相互作用的基础探索到个性化医学临床前检测等截然不同的目标。显然，没有单一的模型能够概括体内情况的复杂性和动态性。关键在于确定关键点，实现特定目标，并设计一个能够验证这些关键点的模型。在本报告中，我们聚焦于癌症进展。我们描述了我们设计的用于模拟浸润期乳腺癌进展的模型。我们选择通过将靶细胞生长在微支架上来为其提供拓扑线索，在将它们嵌入三维基质之前促进极化上皮组织的形成。然后，我们观察这些模型中的细胞组织和分化情况，添加基质细胞，随后添加免疫细胞，以跟踪和量化细胞对药物治疗的反应，包括量化细胞死亡和活力，以及形态发生和侵袭特性。我们使用了包括Comma Dβ、MCF7和MCF10A乳腺上皮细胞系以及来自患者来源异种移植（PDX）的原发性乳腺癌细胞等模型细胞系。我们发现成纤维细胞会影响细胞对多西他赛和帕博西尼的反应。我们还发现NK92免疫细胞可以在三维结构内靶向乳腺癌细胞，从而对细胞毒性进行定量监测。我们还测试了几种细胞外基质来源，并选择了一种基于透明质酸的基质，作为用于原发性人类癌细胞的小鼠肿瘤基底膜提取物的一种有前景的替代品。总体而言，我们验证了一种为乳腺癌设计的用于个性化医学临床前应用的新三维模型。
