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Article

Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling

1
Research Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 603005 Nizhny Novgorod, Russia
2
Lobachevsky State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia
3
Department of Molecular-Genetic Basis of Biotechnology and Protein Engineering, Institute of Molecular Genetics of National Research Centre «Kurchatov Institute», 123182 Moscow, Russia
4
Department of Genomics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of The Russian Academy of Sciences, 117997 Moscow, Russia
5
Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
6
Laboratory of Epigenetics, FSBI «National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov» Ministry of Healthcare of the Russian Federation, 117198 Moscow, Russia
7
National Research Center «Kurchatov Institute», 123182 Moscow, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 8119; https://doi.org/10.3390/ijms21218119
Received: 28 September 2020 / Revised: 22 October 2020 / Accepted: 27 October 2020 / Published: 30 October 2020
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 2.0)
Collagen, the main non-cellular component of the extracellular matrix (ECM), is profoundly reorganized during tumorigenesis and has a strong impact on tumor behavior. The main source of collagen in tumors is cancer-associated fibroblasts. Cancer cells can also participate in the synthesis of ECM; however, the contribution of both types of cells to collagen rearrangements during the tumor progression is far from being clear. Here, we investigated the processes of collagen biosynthesis and remodeling in parallel with the transcriptome changes during cancer cells and fibroblasts interactions. Combining immunofluorescence, RNA sequencing, and second harmonic generation microscopy, we have explored the relationships between the ratio of epithelial (E) and mesenchymal (M) components of hybrid E/M cancer cells, their ability to activate fibroblasts, and the contributions of both cell types to collagen remodeling. To this end, we studied (i) co-cultures of colorectal cancer cells and normal fibroblasts in a collagen matrix, (ii) patient-derived cancer-associated fibroblasts, and (iii) mouse xenograft models. We found that the activation of normal fibroblasts that form dense collagen networks consisting of large, highly oriented fibers depends on the difference in E/M ratio in the cancer cells. The more-epithelial cells activate the fibroblasts more strongly, which correlates with a dense and highly ordered collagen structure in tumors in vivo. The more-mesenchymal cells activate the fibroblasts to a lesser degree; on the other hand, this cell line has a higher innate collagen remodeling capacity. Normal fibroblasts activated by cancer cells contribute to the organization of the extracellular matrix in a way that is favorable for migratory potency. At the same time, in co-culture with epithelial cancer cells, the contribution of fibroblasts to the reorganization of ECM is more pronounced. Therefore, one can expect that targeting the ability of epithelial cancer cells to activate normal fibroblasts may provide a new anticancer therapeutic strategy. View Full-Text
Keywords: cancer-associated fibroblasts; colorectal cancer cells; collagen remodeling; fibroblast activation; epithelial/mesenchymal state cancer-associated fibroblasts; colorectal cancer cells; collagen remodeling; fibroblast activation; epithelial/mesenchymal state
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MDPI and ACS Style

Druzhkova, I.; Shirmanova, M.; Ignatova, N.; Dudenkova, V.; Lukina, M.; Zagaynova, E.; Safina, D.; Kostrov, S.; Didych, D.; Kuzmich, A.; Sharonov, G.; Rakitina, O.; Alekseenko, I.; Sverdlov, E. Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling. Int. J. Mol. Sci. 2020, 21, 8119. https://doi.org/10.3390/ijms21218119

AMA Style

Druzhkova I, Shirmanova M, Ignatova N, Dudenkova V, Lukina M, Zagaynova E, Safina D, Kostrov S, Didych D, Kuzmich A, Sharonov G, Rakitina O, Alekseenko I, Sverdlov E. Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling. International Journal of Molecular Sciences. 2020; 21(21):8119. https://doi.org/10.3390/ijms21218119

Chicago/Turabian Style

Druzhkova, Irina, Marina Shirmanova, Nadezhda Ignatova, Varvara Dudenkova, Maria Lukina, Elena Zagaynova, Dina Safina, Sergey Kostrov, Dmitry Didych, Alexey Kuzmich, George Sharonov, Olga Rakitina, Irina Alekseenko, and Eugene Sverdlov. 2020. "Expression of EMT-Related Genes in Hybrid E/M Colorectal Cancer Cells Determines Fibroblast Activation and Collagen Remodeling" International Journal of Molecular Sciences 21, no. 21: 8119. https://doi.org/10.3390/ijms21218119

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