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

Abstract

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 ofmore » stromal subpopulations.« less

Authors:
ORCiD logo; ORCiD logo; ; ORCiD logo; ORCiD logo; ; ORCiD logo; ORCiD logo; ; ; ORCiD logo
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1605484
Grant/Contract Number:  
[19-SI-003]
Resource Type:
Published Article
Journal Name:
Cancers (Basel)
Additional Journal Information:
[Journal Name: Cancers (Basel) Journal Volume: 12 Journal Issue: 3]; Journal ID: ISSN 2072-6694
Publisher:
MDPI AG
Country of Publication:
Switzerland
Language:
English

Citation Formats

Hum, Nicholas R., Sebastian, Aimy, Gilmore, Sean F., He, Wei, Martin, Kelly A., Hinckley, Aubree, Dubbin, Karen R., Moya, Monica L., Wheeler, Elizabeth K., Coleman, Matthew A., and Loots, Gabriela G. Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo. Switzerland: N. p., 2020. Web. doi:10.3390/cancers12030690.
Hum, Nicholas R., Sebastian, Aimy, Gilmore, Sean F., He, Wei, Martin, Kelly A., Hinckley, Aubree, Dubbin, Karen R., Moya, Monica L., Wheeler, Elizabeth K., Coleman, Matthew A., & Loots, Gabriela G. Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo. Switzerland. doi:10.3390/cancers12030690.
Hum, Nicholas R., Sebastian, Aimy, Gilmore, Sean F., He, Wei, Martin, Kelly A., Hinckley, Aubree, Dubbin, Karen R., Moya, Monica L., Wheeler, Elizabeth K., Coleman, Matthew A., and Loots, Gabriela G. Sat . "Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo". Switzerland. doi:10.3390/cancers12030690.
@article{osti_1605484,
title = {Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo},
author = {Hum, Nicholas R. and Sebastian, Aimy and Gilmore, Sean F. and He, Wei and Martin, Kelly A. and Hinckley, Aubree and Dubbin, Karen R. and Moya, Monica L. and Wheeler, Elizabeth K. and Coleman, Matthew A. and Loots, Gabriela G.},
abstractNote = {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.},
doi = {10.3390/cancers12030690},
journal = {Cancers (Basel)},
number = [3],
volume = [12],
place = {Switzerland},
year = {2020},
month = {3}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.3390/cancers12030690

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