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

Tienderen, Gilles van; Rosmark, Oskar; Lieshout, Ruby; Willemse, Jorke; Weijer, Floor de; Rendin, Linda Elowsson; Westergren‐Thorsson, Gunilla; Doukas, Michail; Koerkamp, B. Groot; Royen, Martin E. van; Laan, L.J. van der; Verstegen, Monique M A

doi:10.1016/j.actbio.2022.11.038

Cited by 22 publications

(20 citation statements)

References 64 publications

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“…An identical decellularization protocol was used for both tissue types. This is based on a previously described method for liver and liver tumor biopsy samples ( 28 ), so that recellularization would be minimally affected by the method of decellularization. Histological evaluation and DNA content quantification revealed successful decellularization ( Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

et al. 2023

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Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions 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. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning aspects. The macro and micro-scale mechanical properties, as determined by rheology and micro-indentation, revealed the local heterogeneity of the ECM. When growing CCAOs in decellularized lung and lymph nodes genes related to metastatic processes, including epithelial-to-mesenchymal transition and cancer stem cell plasticity, were significantly influenced by the ECM in an organ-specific manner. Furthermore, CCAOs exhibit significant differences in migration and proliferation dynamics dependent on the original patient tumor and donor of the target organ. In conclusion, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. Convergence of CCAOs with the ECM of its metastatic organs provide a new platform for mechanistic study of cancer metastasis.

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Section: Resultsmentioning

confidence: 99%

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

et al. 2023

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“…134 The use of native ECM by decellularization from native tumor and liver scaffolds had been reported in cholangiocarcinoma, which had a better resemblance to the original tumor TME than ordinary BME. 135,136 Dynamic cell culture like magnetic levitation is an alternative way to create organoids, where cells are suspended with magnetic beads and organoids are generated under magnetic field. 137,138 It was postulated that the cell aggregates could be more homogeneous, and the rotating magnetic field may also mimic the mechanical forces of blood flow.…”

Section: Other Novel Methodsmentioning

confidence: 99%

“…New scaffolding materials like recombinant silk microfiber have been used to generate mature human brain organoids, which could facilitate the delivery of oxygen and nutrients, promote self‐assembly, and reduce heterogeneity of cellular organization compared to organoids without silk scaffold 134 . The use of native ECM by decellularization from native tumor and liver scaffolds had been reported in cholangiocarcinoma, which had a better resemblance to the original tumor TME than ordinary BME 135,136 …”

Section: Future Perspectivesmentioning

confidence: 99%

Patient‐derived organoid culture in epithelial ovarian cancers—Techniques, applications, and future perspectives

Chan,

Mo,

et al. 2023

Cancer Medicine

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Epithelial ovarian cancer (EOC) is a heterogeneous disease composed of different cell types with different molecular aberrations. Traditional cell lines and mice models cannot recapitulate the human tumor biology and tumor microenvironment (TME). Patient‐derived organoids (PDOs) are freshly derived from patients' tissues and are then cultured with extracellular matrix and conditioned medium. The high concordance of epigenetic, genomic, and proteomic landscapes between the parental tumors and PDOs suggests that PDOs can provide more reliable results in studying cancer biology, allowing high throughput drug screening, and identifying their associated signaling pathways and resistance mechanisms. However, despite having a heterogeneity of cells in PDOs, some cells in TME will be lost during the culture process. Next‐generation organoids have been developed to circumvent some of the limitations. Genetically engineered organoids involving targeted gene editing can facilitate the understanding of tumorigenesis and drug response. Co‐culture systems where PDOs are cultured with different cell components like immune cells can allow research using immunotherapy which is otherwise impossible in conventional cell lines. In this review, the limitations of the traditional in vitro and in vivo assays, the use of PDOs, the challenges including some tips and tricks of PDO generation in EOC, and the future perspectives, will be discussed.

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“…Tienderen and colleagues exploited tumor tissue‐derived dECM to culture cholangiocarcinoma organoids and found that the tumor ECM induced a transcriptome profile more closely resembling patient tumor tissue than BME or normal tissue ECM. [ 100 ] Notably, hydrogel‐based microwell arrays with a U shape were engineered by Lutolf group [ 101 ] for high throughput generation of patient‐derived colorectal cancer organoids as they are superior in standardization and reproducibility compared to the traditional 3D‐culture setting. To confirm the potential of their approach in high‐content phenotypic drug testing, 80 anticancer compounds were tested to determine their efficacy.…”

Section: Strategies For Physiologically Relevant 3d Modelsmentioning

confidence: 99%

3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip

Zhou

et al. 2023

Adv Healthcare Materials

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Decades of efforts in engineering in vitro cancer models have advanced drug discovery and the insight into cancer biology. However, the establishment of preclinical models that enable fully recapitulating the tumor microenvironment remains challenging owing to its intrinsic complexity. Recent progress in engineering techniques has allowed the development of a new generation of in vitro preclinical models that can recreate complex in vivo tumor microenvironments and accurately predict drug responses, including spheroids, organoids, and tumor‐on‐a‐chip. These biomimetic 3D tumor models are of particular interest as they pave the way for better understanding of cancer biology and accelerating the development of new anticancer therapeutics with reducing animal use. Here, the recent advances in developing these in vitro platforms for cancer modeling and preclinical drug screening, focusing on incorporating hydrogels are reviewed to reconstitute physiologically relevant microenvironments. The combination of spheroids/organoids with microfluidic technologies is also highlighted to better mimic in vivo tumors and discuss the challenges and future directions in the clinical translation of such models for drug screening and personalized medicine.

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

Cited by 22 publications

References 64 publications

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes

Patient‐derived organoid culture in epithelial ovarian cancers—Techniques, applications, and future perspectives

3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip

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