Dataset Information

Patient-derived model combining organoids and matrix reveals cholangiocarcinoma promoting properties of the microenvironment

ABSTRACT: Cholangiocarcinoma (CCA) is a rare but aggressive type of primary liver cancer, with an overall 5-year survival rate of <10%. The extracellular matrix (ECM) plays a particularly important role in CCA tumor biology, manifested in the desmoplastic tumor environment. This study aim is to design an in vitro CCA model combining patient-derived cells and patient-derived ECM mimicking the native microenvironment. decellularized Patient CCA tissue (CCA-matrix; CCA-M) and tumor-free liver tissue (TFL-M) was decellularized and repopulated with CCA organoids (CCAOs). Culture was performed with amino acids labeled with stable heavy isotopes to enable separation of pre-existing ECM from proteins produced by the cells in the mass spectrometry (MS) analysis. CCAOs on decellularized matrix form complex morphological structures, with environment-dependent proliferation and migration dynamics, driven by the occurrence of EMT. CCAOs in TFL-M or CCA-M can be used to study the initiation or progression of desmoplasia in CCA, respectively. Furthermore, in-depth transcriptomic and proteomic analysis reveals that CCA-M induces a transcriptome more resembling in vivo CCA tumor tissue, with an accompanying protective effect of the desmoplastic environment on tumor survival.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

DISEASE(S): Cholangiocarcinoma

SUBMITTER: Oskar Rosmark

LAB HEAD: Prof. Luc van der Laan

PROVIDER: PXD028408 | Pride | 2023-03-04

REPOSITORIES: Pride

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Publications

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

van Tienderen Gilles S GS Rosmark Oskar O Lieshout Ruby R Willemse Jorke J de Weijer Floor F Elowsson Rendin Linda L Westergren-Thorsson Gunilla G Doukas Michail M Groot Koerkamp Bas B van Royen Martin E ME van der Laan Luc Jw LJ Verstegen Monique Ma MM

Acta biomaterialia 20221123

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 s ...[more]

PMID: 36427688

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Project description:Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization Background & Aims: Cholangiocarcinoma (CCA) is a hepatobiliary malignancy with dismal prognosis. Currently available models fail to recapitulate the full complexity of CCA, particularly the desmoplastic environment and the interplay between cancer cells and the extracellular matrix (ECM). We aimed to study the role of epithelial tumor cells in ECM deposition and desmoplasia by designing a model encompassing primary epithelial CCA organoids (CCAOs) and native liver and tumor scaffolds obtained by decellularization. Results: Decellularization resulted in effective removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. When culturing CCAOs in CCA-M, compared to TFL-M and BME, the genome-wide gene expression profile much more resembled the transcriptome of primary CCA tumor tissue in vivo, with an accompanying increase in chemoresistance. CCAOs in decellularized matrix, both CCA-M and TFL-M, exhibited the formation of complex morphological structures, and revealed environment-dependent proliferation and migration dynamics, driven by the occurrence of epithelial-mesenchymal transition (EMT). CCA-M induced specific extracellular matrix protein production in CCAOs, such as fibronectin 1 (FN1), which is related to desmoplasia and patient survival. In TFL-M, lacking the desmoplastic environment, CCAOs were able to initiate a desmoplastic reaction directly through increased production of multiple collagen types. Conclusions: This improved model of cholangiocarcinoma, combining organoids and native extracellular matrix, recapitulates key components of CCA tumor biology, including transcriptome profiles, migration patterns, EMT, and ECM protein production. The increased production of extracellular matrix proteins suggests that epithelial tumor cells can contribute to their own desmoplastic environment.

Project description:Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. Current treatment options are limited, with surgical resection or transplantation the only possibility with curative intent. This becomes unavailable if CCA metastasizes to distant organs, most commonly lung and lymph nodes, which in turn drastically reduces overall survival. Clinically, these metastatic sites have a distinct impact on prognosis and survival, however mechanistic insight is lacking. This is partly due to currently available models that fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interaction between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. This includes a tissue-specific ECM protein signature and macro and micro-scale mechanical properties, which reveal the local heterogeneity of the ECM. After recellularization, gene expression analysis showed metastasis-related processes, including epithelial-to-mesenchymal transition, cancer stem cell plasticity, and ECM production, are significantly influenced by the ECM in an organ-specific manner. Furthermore, we find that CCAOs exhibit significant differences in migration and proliferation dynamics depending on metastatic site, the original patient tumor, and donor of target organ. Thus, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. In conclusion, convergence of CCAOs with its organ-specific location of metastasis, obtained by decellularization, provides a valuable tool for research on metastatic colonization in CCA.

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	CCA14_scaf_BME.raw	Raw
	CCA14_scaf_H.raw	Raw
	CCA14_scaf_T.raw	Raw
	CCA1_scaf_BME.raw	Raw
	CCA1_scaf_H.raw	Raw