Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

被引:18
作者
Hum, Nicholas R. [1 ,2 ]
Sebastian, Aimy [1 ]
Gilmore, Sean F. [1 ]
He, Wei [1 ]
Martin, Kelly A. [1 ]
Hinckley, Aubree [1 ]
Dubbin, Karen R. [3 ]
Moya, Monica L. [3 ]
Wheeler, Elizabeth K. [3 ]
Coleman, Matthew A. [1 ,4 ]
Loots, Gabriela G. [1 ,2 ,4 ]
机构
[1] Lawrence Livermore Natl Lab, Phys & Life Sci Directorate, Livermore, CA 94550 USA
[2] Univ Calif Merced, Sch Nat Sci, Merced, CA 94550 USA
[3] Lawrence Livermore Natl Lab, Engn Directorate, Livermore, CA 94550 USA
[4] Univ Calif Davis, Dept Biochem & Mol Med, Sacramento, CA 95817 USA
关键词
syngeneic culture; PDX; spheroid; tumoroid; monolayer culture; RNA-seq; TNBC; 4T1; single-cell RNA-seq; EMT; MODELS; OPPORTUNITIES; CELLS; EMT;
D O I
10.3390/cancers12030690
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Current pre-clinical models of cancer fail to recapitulate the cancer cell behavior in primary tumors primarily because of the lack of a deeper understanding of the effects that the microenvironment has on cancer cell phenotype. Transcriptomic profiling of 4T1 murine mammary carcinoma cells from 2D and 3D cultures, subcutaneous or orthotopic allografts (from immunocompetent or immunodeficient mice), as well as ex vivo tumoroids, revealed differences in molecular signatures including altered expression of genes involved in cell cycle progression, cell signaling and extracellular matrix remodeling. The 3D culture platforms had more in vivo-like transcriptional profiles than 2D cultures. In vivo tumors had more cells undergoing epithelial-to-mesenchymal transition (EMT) while in vitro cultures had cells residing primarily in an epithelial or mesenchymal state. Ex vivo tumoroids incorporated aspects of in vivo and in vitro culturing, retaining higher abundance of cells undergoing EMT while shifting cancer cell fate towards a more mesenchymal state. Cellular heterogeneity surveyed by scRNA-seq revealed that ex vivo tumoroids, while rapidly expanding cancer and fibroblast populations, lose a significant proportion of immune components. This study emphasizes the need to improve in vitro culture systems and preserve syngeneic-like tumor composition by maintaining similar EMT heterogeneity as well as inclusion of stromal subpopulations.
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页数:23
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