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Extracellular matrix drives tumor organoids toward desmoplastic matrix deposition and mesenchymal transition

van Tienderen, Gilles S ; Rosmark, Oskar LU orcid ; Lieshout, Ruby ; Willemse, Jorke ; de Weijer, Floor ; Rendin, Linda Elowsson LU ; Westergren-Thorsson, Gunilla LU ; Doukas, Michail ; Koerkamp, Bas Groot and van Royen, Martin E , et al. (2023) In Acta Biomaterialia 158. p.115-131
Abstract

Patient-derived tumor organoids have been established as promising tools for in vitro modelling of multiple tumors, including cholangiocarcinoma (CCA). However, organoids are commonly cultured in basement membrane extract (BME) which does not recapitulate the intricacies of the extracellular matrix (ECM). We combined CCA organoids (CCAOs) with native tumor and liver scaffolds, obtained by decellularization, to effectuate a model to study the interaction between epithelial tumor cells and their surrounding ECM. Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin, including stiffness and presence of desmoplasia. The transcriptome of CCAOs in a tumor... (More)

Patient-derived tumor organoids have been established as promising tools for in vitro modelling of multiple tumors, including cholangiocarcinoma (CCA). However, organoids are commonly cultured in basement membrane extract (BME) which does not recapitulate the intricacies of the extracellular matrix (ECM). We combined CCA organoids (CCAOs) with native tumor and liver scaffolds, obtained by decellularization, to effectuate a model to study the interaction between epithelial tumor cells and their surrounding ECM. Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin, including stiffness and presence of desmoplasia. The transcriptome of CCAOs in a tumor scaffold much more resembled that of patient-paired CCA tissue in vivo compared to CCAOs cultured in BME or liver scaffolds. This was accompanied by an increase in chemoresistance to clinically-relevant chemotherapeutics. CCAOs in decellularized scaffolds revealed environment-dependent proliferation dynamics, driven by the occurrence of epithelial-mesenchymal transition. Furthermore, CCAOs initiated an environment-specific desmoplastic reaction by increasing production of multiple collagen types. In conclusion, convergence of organoid-based models with native ECM scaffolds will lead to better understanding of the in vivo tumor environment. STATEMENT OF SIGNIFICANCE: The extracellular matrix (ECM) influences various facets of tumor behavior. Understanding the exact role of the ECM in controlling tumor cell fate is pertinent to understand tumor progression and develop novel therapeutics. This is particularly the case for cholangiocarcinoma (CCA), whereby the ECM displays a distinct tumor environment, characterized by desmoplasia. However, current models to study the interaction between epithelial tumor cells and the environment are lacking. We have developed a fully patient-derived model encompassing CCA organoids (CCAOs) and human decellularized tumor and tumor-free liver ECM. The tumor ECM induced recapitulation of various aspects of CCA, including migration dynamics, transcriptome and proteome profiles, and chemoresistance. Lastly, we uncover that epithelial tumor cells contribute to matrix deposition, and that this phenomenon is dependent on the level of desmoplasia already present.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Acta Biomaterialia
volume
158
pages
115 - 131
publisher
Elsevier
external identifiers
  • scopus:85146314206
  • pmid:36427688
ISSN
1878-7568
DOI
10.1016/j.actbio.2022.11.038
language
English
LU publication?
yes
additional info
Copyright © 2022. Published by Elsevier Ltd.
id
35e92944-44a1-4a60-b7c6-ab30536b7567
date added to LUP
2022-12-22 17:04:52
date last changed
2024-04-18 17:40:25
@article{35e92944-44a1-4a60-b7c6-ab30536b7567,
  abstract     = {{<p>Patient-derived tumor organoids have been established as promising tools for in vitro modelling of multiple tumors, including cholangiocarcinoma (CCA). However, organoids are commonly cultured in basement membrane extract (BME) which does not recapitulate the intricacies of the extracellular matrix (ECM). We combined CCA organoids (CCAOs) with native tumor and liver scaffolds, obtained by decellularization, to effectuate a model to study the interaction between epithelial tumor cells and their surrounding ECM. Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin, including stiffness and presence of desmoplasia. The transcriptome of CCAOs in a tumor scaffold much more resembled that of patient-paired CCA tissue in vivo compared to CCAOs cultured in BME or liver scaffolds. This was accompanied by an increase in chemoresistance to clinically-relevant chemotherapeutics. CCAOs in decellularized scaffolds revealed environment-dependent proliferation dynamics, driven by the occurrence of epithelial-mesenchymal transition. Furthermore, CCAOs initiated an environment-specific desmoplastic reaction by increasing production of multiple collagen types. In conclusion, convergence of organoid-based models with native ECM scaffolds will lead to better understanding of the in vivo tumor environment. STATEMENT OF SIGNIFICANCE: The extracellular matrix (ECM) influences various facets of tumor behavior. Understanding the exact role of the ECM in controlling tumor cell fate is pertinent to understand tumor progression and develop novel therapeutics. This is particularly the case for cholangiocarcinoma (CCA), whereby the ECM displays a distinct tumor environment, characterized by desmoplasia. However, current models to study the interaction between epithelial tumor cells and the environment are lacking. We have developed a fully patient-derived model encompassing CCA organoids (CCAOs) and human decellularized tumor and tumor-free liver ECM. The tumor ECM induced recapitulation of various aspects of CCA, including migration dynamics, transcriptome and proteome profiles, and chemoresistance. Lastly, we uncover that epithelial tumor cells contribute to matrix deposition, and that this phenomenon is dependent on the level of desmoplasia already present.</p>}},
  author       = {{van Tienderen, Gilles S and Rosmark, Oskar and Lieshout, Ruby and Willemse, Jorke and de Weijer, Floor and Rendin, Linda Elowsson and Westergren-Thorsson, Gunilla and Doukas, Michail and Koerkamp, Bas Groot and van Royen, Martin E and van der Laan, Luc Jw and Verstegen, Monique Ma}},
  issn         = {{1878-7568}},
  language     = {{eng}},
  pages        = {{115--131}},
  publisher    = {{Elsevier}},
  series       = {{Acta Biomaterialia}},
  title        = {{Extracellular matrix drives tumor organoids toward desmoplastic matrix deposition and mesenchymal transition}},
  url          = {{http://dx.doi.org/10.1016/j.actbio.2022.11.038}},
  doi          = {{10.1016/j.actbio.2022.11.038}},
  volume       = {{158}},
  year         = {{2023}},
}