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@article{2365017,
author = {Atanasova, Velina S and Cardona, Crhistian de Jesus and Hejret, Václav and Tiefenbacher, Andreas and Mair, Theresia and Tran, Loan and Pfneissl, Janette and Draganic, Kristina and Binder, Carina and Kabiljo, Julijan and Clement, Janik and Woeran, Katharina and Neudert, Barbara and Wohlhaupter, Sabrina and Haase, Astrid and Domazet, Sandra and Hengstschlaeger, Markus and Mitterhauser, Markus and Muellauer, Leonhard and Tichý, Boris and Bergmann, Michael and Schweikert, Gabriele and Hartl, Markus and Dolznig, Helmut and Egger, Gerda},
article_location = {UNITED STATES},
article_number = {6},
doi = {http://dx.doi.org/10.1016/j.jcmgh.2023.02.014},
keywords = {Colorectal Cancer; Fibroblasts; Organoids; targeted therapy},
language = {eng},
issn = {2352-345X},
journal = {CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY},
title = {Mimicking Tumor Cell Heterogeneity of Colorectal Cancer in a Patient-derived Organoid-Fibroblast Model},
url = {https://www.sciencedirect.com/science/article/pii/S2352345X2300036X?via%3Dihub},
volume = {15},
year = {2023}
}
TY - JOUR
ID - 2365017
AU - Atanasova, Velina S - Cardona, Crhistian de Jesus - Hejret, Václav - Tiefenbacher, Andreas - Mair, Theresia - Tran, Loan - Pfneissl, Janette - Draganic, Kristina - Binder, Carina - Kabiljo, Julijan - Clement, Janik - Woeran, Katharina - Neudert, Barbara - Wohlhaupter, Sabrina - Haase, Astrid - Domazet, Sandra - Hengstschlaeger, Markus - Mitterhauser, Markus - Muellauer, Leonhard - Tichý, Boris - Bergmann, Michael - Schweikert, Gabriele - Hartl, Markus - Dolznig, Helmut - Egger, Gerda
PY - 2023
TI - Mimicking Tumor Cell Heterogeneity of Colorectal Cancer in a Patient-derived Organoid-Fibroblast Model
JF - CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
VL - 15
IS - 6
SP - 1391-1419
EP - 1391-1419
PB - ELSEVIER INC
SN - 2352345X
KW - Colorectal Cancer
KW - Fibroblasts
KW - Organoids
KW - targeted therapy
UR - https://www.sciencedirect.com/science/article/pii/S2352345X2300036X?via%3Dihub
N2 - BACKGROUND & AIMS: Patient-derived organoid cancer models are generated from epithelial tumor cells and reflect tumor characteristics. However, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we developed a colorectal cancer organoid model that incorporates matched epithelial cells and stromal fibroblasts. METHODS: Primary fibroblasts and tumor cells were isolated from colorectal cancer specimens. Fibroblasts were character-ized for their proteome, secretome, and gene expression sig-natures. Fibroblast/organoid co-cultures were analyzed by immunohistochemistry and compared with their tissue of origin, as well as on gene expression levels compared with standard organoid models. Bioinformatics deconvolution was used to calculate cellular proportions of cell subsets in orga-noids based on single-cell RNA sequencing data. RESULTS: Normal primary fibroblasts, isolated from tumor adjacent tissue, and cancer associated fibroblasts retained their molecular characteristics in vitro, including higher motility of cancer associated compared with normal fibroblasts. Impor-tantly, both cancer-associated fibroblasts and normal fibro-blasts supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. Organoids grown together with fibroblasts displayed a larger cellular heteroge-neity of tumor cells compared with mono-cultures and closely resembled the in vivo tumor morphology. Additionally, we observed a mutual crosstalk between tumor cells and fibro-blasts in the co-cultures. This was manifested by considerably deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. Thrombospondin-1 was identified as a critical factor for fibro-blast invasiveness. CONCLUSION: We developed a physiological tumor/stroma model, which will be vital as a personalized tumor model to study disease mechanisms and therapy response in colorectal cancer. (Cell Mol Gastroenterol Hepatol 2023;15:1391-1419; https://doi.org/10.1016/j.jcmgh.2023.02.014)
ER -
ATANASOVA, Velina S, Crhistian de Jesus CARDONA, Václav HEJRET, Andreas TIEFENBACHER, Theresia MAIR, Loan TRAN, Janette PFNEISSL, Kristina DRAGANIC, Carina BINDER, Julijan KABILJO, Janik CLEMENT, Katharina WOERAN, Barbara NEUDERT, Sabrina WOHLHAUPTER, Astrid HAASE, Sandra DOMAZET, Markus HENGSTSCHLAEGER, Markus MITTERHAUSER, Leonhard MUELLAUER, Boris TICHÝ, Michael BERGMANN, Gabriele SCHWEIKERT, Markus HARTL, Helmut DOLZNIG and Gerda EGGER. Mimicking Tumor Cell Heterogeneity of Colorectal Cancer in a Patient-derived Organoid-Fibroblast Model. \textit{CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY}. UNITED STATES: ELSEVIER INC, 2023, vol.~15, No~6, p.~1391-1419. ISSN~2352-345X. Available from: https://dx.doi.org/10.1016/j.jcmgh.2023.02.014.
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