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      3D bioprinted CRC model brings to light the replication necessity of an oncolytic vaccinia virus encoding FCU1 gene to exert an efficient anti-tumoral activity

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          Abstract

          The oncolytic virus represents a promising therapeutic strategy involving the targeted replication of viruses to eliminate cancer cells, while preserving healthy ones. Despite ongoing clinical trials, this approach encounters significant challenges. This study delves into the interaction between an oncolytic virus and extracellular matrix mimics (ECM mimics). A three-dimensional colorectal cancer model, enriched with ECM mimics through bioprinting, was subjected to infection by an oncolytic virus derived from the vaccinia virus (oVV). The investigation revealed prolonged expression and sustained oVV production. However, the absence of a significant antitumor effect suggested that the virus’s progression toward non-infected tumoral clusters was hindered by the ECM mimics. Effective elimination of tumoral cells was achieved by introducing an oVV expressing FCU1 (an enzyme converting the prodrug 5-FC into the chemotherapeutic compound 5-FU) alongside 5-FC. Notably, this efficacy was absent when using a non-replicative vaccinia virus expressing FCU1. Our findings underscore then the crucial role of oVV proliferation in a complex ECM mimics. Its proliferation facilitates payload expression and generates a bystander effect to eradicate tumors. Additionally, this study emphasizes the utility of 3D bioprinting for assessing ECM mimics impact on oVV and demonstrates how enhancing oVV capabilities allows overcoming these barriers. This showcases the potential of 3D bioprinting technology in designing purpose-fit models for such investigations.

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          Most cited references40

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          Tumour heterogeneity and resistance to cancer therapies

          Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies.
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            Matrix metalloproteinases: regulators of the tumor microenvironment.

            Extracellular proteolysis mediates tissue homeostasis. In cancer, altered proteolysis leads to unregulated tumor growth, tissue remodeling, inflammation, tissue invasion, and metastasis. The matrix metalloproteinases (MMPs) represent the most prominent family of proteinases associated with tumorigenesis. Recent technological developments have markedly advanced our understanding of MMPs as modulators of the tumor microenvironment. In addition to their role in extracellular matrix turnover and cancer cell migration, MMPs regulate signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner. These aspects of MMP function are reorienting our approaches to cancer therapy. Copyright 2010 Elsevier Inc. All rights reserved.
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              Organoids in cancer research

              The recent advances in in vitro 3D culture technologies, such as organoids, have opened new avenues for the development of novel, more physiological human cancer models. Such preclinical models are essential for more efficient translation of basic cancer research into novel treatment regimens for patients with cancer. Wild-type organoids can be grown from embryonic and adult stem cells and display self-organizing capacities, phenocopying essential aspects of the organs they are derived from. Genetic modification of organoids allows disease modelling in a setting that approaches the physiological environment. Additionally, organoids can be grown with high efficiency from patient-derived healthy and tumour tissues, potentially enabling patient-specific drug testing and the development of individualized treatment regimens. In this Review, we evaluate tumour organoid protocols and how they can be utilized as an alternative model for cancer research.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/684568Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
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                URI : https://loop.frontiersin.org/people/2716158Role: Role: Role:
                URI : https://loop.frontiersin.org/people/2685791Role: Role:
                URI : https://loop.frontiersin.org/people/2655246Role:
                URI : https://loop.frontiersin.org/people/2681161Role: Role: Role: Role: Role:
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                18 July 2024
                2024
                : 14
                : 1384499
                Affiliations
                [1] 1 3d.FAB, CNRS, INSA, Univ Lyon, CPE-Lyon, UMR5246, ICBMS, Université Lyon 1 , Villeurbanne, France
                [2] 2 Transgene SA , Illkirch-Graffenstaden, France
                Author notes

                Edited by: Alessandro Passardi, Scientific Institute of Romagna for the Study and Treatment of Tumors (IRCCS), Italy

                Reviewed by: Zoltan Janos Vereb, University of Szeged, Hungary

                Laura Russo, University of Milano-Bicocca, Italy

                *Correspondence: Christophe A. Marquette, christophe.marquette@ 123456univ-lyon1.fr ; Philippe Erbs, erbs@ 123456transgene.fr
                Article
                10.3389/fonc.2024.1384499
                11292208
                39091906
                15ec050d-8222-4341-a4e3-a2dd6ecbf245
                Copyright © 2024 Marquette, Petiot, Spindler, Ebel, Nzepa, Moreau, Erbs, Balloul, Quemeneur and Zaupa

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 February 2024
                : 04 July 2024
                Page count
                Figures: 4, Tables: 0, Equations: 4, References: 40, Pages: 11, Words: 6972
                Funding
                The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
                Categories
                Oncology
                Original Research
                Custom metadata
                Gastrointestinal Cancers: Colorectal Cancer

                Oncology & Radiotherapy
                bioprinting,tumor,colorectal (colon) cancer,oncovirus,hydrogel
                Oncology & Radiotherapy
                bioprinting, tumor, colorectal (colon) cancer, oncovirus, hydrogel

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