Multi-omics analysis based on 3D-bioprinted models innovates therapeutic target discovery of osteosarcoma

Lin, Yixuan; Yang, Yiqi; Yuan, Kai; Yang, Shengbing; Zhang, Shuhong; Li, Hanjun; Tang, Tian

doi:10.1016/j.bioactmat.2022.03.029

Cited by 18 publications

(23 citation statements)

References 62 publications

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“…[65,[68][69][70][71][72]. Modelling the complexity of tumour progression, especially the steps of metastasis formation, also requires microfluidics and several host tissues to be combined in novel in vitro test systems [82][83][84][85][86][87][88][89][90][91][92][93]. The continuously emerging data about such devices for BC and more complex BC models were summarised by Moccia and Haase [94,95].…”

Section: Discussionmentioning

confidence: 99%

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

Dankó

Petővári

Raffay

et al. 2022

IJMS

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Monolayer cultures, the less standard three-dimensional (3D) culturing systems, and xenografts are the main tools used in current basic and drug development studies of cancer research. The aim of biofabrication is to design and construct a more representative in vivo 3D environment, replacing two-dimensional (2D) cell cultures. Here, we aim to provide a complex comparative analysis of 2D and 3D spheroid culturing, and 3D bioprinted and xenografted breast cancer models. We established a protocol to produce alginate-based hydrogel bioink for 3D bioprinting and the long-term culturing of tumour cells in vitro. Cell proliferation and tumourigenicity were assessed with various tests. Additionally, the results of rapamycin, doxycycline and doxorubicin monotreatments and combinations were also compared. The sensitivity and protein expression profile of 3D bioprinted tissue-mimetic scaffolds showed the highest similarity to the less drug-sensitive xenograft models. Several metabolic protein expressions were examined, and the in situ tissue heterogeneity representing the characteristics of human breast cancers was also verified in 3D bioprinted and cultured tissue-mimetic structures. Our results provide additional steps in the direction of representing in vivo 3D situations in in vitro studies. Future use of these models could help to reduce the number of animal experiments and increase the success rate of clinical phase trials.

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Section: Discussionmentioning

confidence: 99%

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

Dankó

Petővári

Raffay

et al. 2022

IJMS

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“…(A) (B) Although 3D-bioprinting has been used in studies focusing on various forms of solid tumors, including neuroblastoma [66,67], melanoma [68,69], pancreatic cancer [55,70], non-small cell lung cancer [71], liver cancer [72], and osteosarcoma [73], the most prolific research has been conducted in breast cancer and glioma/glioblastoma models. The level of control over the spatial arrangement of cells, the possibility of multiple cell type use, and fine-tuning the biochemical and physical properties of biomaterials available through bioprinting allows generation of structures of a varied degree of complexity-from simple monocellular models to organoids and assembloids.…”

Section: D-bioprinting Applications In Solid Tumor Microenvironment R...mentioning

confidence: 99%

“…Although 3D-bioprinting has been used in studies focusing on various forms of solid tumors, including neuroblastoma [66,67], melanoma [68,69], pancreatic cancer [55,70], non-small cell lung cancer [71], liver cancer [72], and osteosarcoma [73], the most prolific research has been conducted in breast cancer and glioma/glioblastoma models.…”

Section: D-bioprinting Applications In Solid Tumor Microenvironment R...mentioning

confidence: 99%

Perspectives for 3D-Bioprinting in Modeling of Tumor Immune Evasion

Staros

Michalak

Rusinek

et al. 2022

Cancers

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In a living organism, cancer cells function in a specific microenvironment, where they exchange numerous physical and biochemical cues with other cells and the surrounding extracellular matrix (ECM). Immune evasion is a clinically relevant phenomenon, in which cancer cells are able to direct this interchange of signals against the immune effector cells and to generate an immunosuppressive environment favoring their own survival. A proper understanding of this phenomenon is substantial for generating more successful anticancer therapies. However, classical cell culture systems are unable to sufficiently recapture the dynamic nature and complexity of the tumor microenvironment (TME) to be of satisfactory use for comprehensive studies on mechanisms of tumor immune evasion. In turn, 3D-bioprinting is a rapidly evolving manufacture technique, in which it is possible to generate finely detailed structures comprised of multiple cell types and biomaterials serving as ECM-analogues. In this review, we focus on currently used 3D-bioprinting techniques, their applications in the TME research, and potential uses of 3D-bioprinting in modeling of tumor immune evasion and response to immunotherapies.

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“…Nevertheless, we expanded the in vitro assays to additional osteosarcoma cells in a 2D monolayer culture to ascertain their growth inhibition profiles. While some studies on sarcoma have utilized 3D models for drug testing [ 28 , 29 ], the marked effect of liver metabolism on the activity of the molecules under study dictated the use of an in vivo model, which we chose to perform with the Saos-2 cell line. Herein, we challenge the hypothesis that the in vivo metabolism of 6-N,N-di-substituted derivatives into mono-substituted combi-molecules could enhance the potency of the dual EGFR-DNA-targeting mechanism by sustaining high concentrations of the dual-acting EGFR-DNA targeting species in tumor cells in vivo.…”

Section: Introductionmentioning

confidence: 99%

Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model

Facchin

Fraga-Timiraos

Schmitt

et al. 2023

Cells

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Background: ZR2002 is a dual EGFR-DNA-targeting combi-molecule that carries a chloroethyl group at the six-position of the quinazoline ring designed to alkylate DNA. Despite its good pharmacokinetics, ZR2002 is metabolized in vivo into dechlorinated metabolites, losing the DNA-alkylating function required to damage DNA. To increase the DNA damage activity in tumor cells in vivo, we compared ZR2002 with two of its 6-N,N-disubstituted analogs: “JS61”, with a nitrogen mustard function at the six-position of the quinazoline ring, and “JS84”, with an N-methyl group. Methods: Tumor xenografts were performed with the human Saos-2 osteosarcoma cell line expressing EGFR. Mice were treated with ZR2002, JS84 or JS61, and the tumor burden was measured with a caliper and CT/PET imaging. Drug metabolism was analyzed with LC-MS. EGFR and ɣ-H2AX phosphorylation were quantified via Western blot analysis and immunohistochemistry. Results: In vivo analysis showed that significant tumor growth inhibition was only achieved when ZR2002 was administered in its naked form. The metabolic dealkylation of JS61 and JS84 did not release sufficient concentrations of ZR2002 for the intratumoral inhibition of P-EGFR or enhanced levels of P-H2AX. Conclusions: The results in toto suggest that intratumoral concentrations of intact ZR2002 are correlated with the highest inhibition of P-EGFR and induction of DNA damage in vivo. ZR2002 may well represent a good drug candidate for the treatment of EGFR-expressing osteosarcoma.

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Multi-omics analysis based on 3D-bioprinted models innovates therapeutic target discovery of osteosarcoma

Cited by 18 publications

References 62 publications

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

Characterisation of 3D Bioprinted Human Breast Cancer Model for In Vitro Drug and Metabolic Targeting

Perspectives for 3D-Bioprinting in Modeling of Tumor Immune Evasion

Molecular Analysis of the Superior Efficacy of a Dual Epidermal Growth Factor Receptor (EGFR)-DNA-Targeting Combi-Molecule in Comparison with Its Putative Prodrugs 6-Mono-Alkylamino- and 6,6-Dialkylaminoquinazoline in a Human Osteosarcoma Xenograft Model

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