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      Patient-derived xenograft (PDX) models, applications and challenges in cancer research

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          Abstract

          The establishing of the first cancer models created a new perspective on the identification and evaluation of new anti-cancer therapies in preclinical studies. Patient-derived xenograft models are created by tumor tissue engraftment. These models accurately represent the biology and heterogeneity of different cancers and recapitulate tumor microenvironment. These features have made it a reliable model along with the development of humanized models. Therefore, they are used in many studies, such as the development of anti-cancer drugs, co-clinical trials, personalized medicine, immunotherapy, and PDX biobanks. This review summarizes patient-derived xenograft models development procedures, drug development applications in various cancers, challenges and limitations.

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          Ultrastructural Characterization of the Lower Motor System in a Mouse Model of Krabbe Disease

          Valentina Cappello, Laura Marchetti, Paola Parlanti … (2016)
          Krabbe disease (KD) is a neurodegenerative disorder caused by the lack of β- galactosylceramidase enzymatic activity and by widespread accumulation of the cytotoxic galactosyl-sphingosine in neuronal, myelinating and endothelial cells. Despite the wide use of Twitcher mice as experimental model for KD, the ultrastructure of this model is partial and mainly addressing peripheral nerves. More details are requested to elucidate the basis of the motor defects, which are the first to appear during KD onset. Here we use transmission electron microscopy (TEM) to focus on the alterations produced by KD in the lower motor system at postnatal day 15 (P15), a nearly asymptomatic stage, and in the juvenile P30 mouse. We find mild effects on motorneuron soma, severe ones on sciatic nerves and very severe effects on nerve terminals and neuromuscular junctions at P30, with peripheral damage being already detectable at P15. Finally, we find that the gastrocnemius muscle undergoes atrophy and structural changes that are independent of denervation at P15. Our data further characterize the ultrastructural analysis of the KD mouse model, and support recent theories of a dying-back mechanism for neuronal degeneration, which is independent of demyelination.
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            Landscape of somatic mutations in 560 breast cancer whole genome sequences

            Serena Nik-Zainal, Helen Davies, Johan Staaf … (2016)
            We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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              Extracellular matrix degradation and remodeling in development and disease.

              Pengfei Lu, Ken Takai, Valerie Weaver … (2011)
              The extracellular matrix (ECM) serves diverse functions and is a major component of the cellular microenvironment. The ECM is a highly dynamic structure, constantly undergoing a remodeling process where ECM components are deposited, degraded, or otherwise modified. ECM dynamics are indispensible during restructuring of tissue architecture. ECM remodeling is an important mechanism whereby cell differentiation can be regulated, including processes such as the establishment and maintenance of stem cell niches, branching morphogenesis, angiogenesis, bone remodeling, and wound repair. In contrast, abnormal ECM dynamics lead to deregulated cell proliferation and invasion, failure of cell death, and loss of cell differentiation, resulting in congenital defects and pathological processes including tissue fibrosis and cancer. Understanding the mechanisms of ECM remodeling and its regulation, therefore, is essential for developing new therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.
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                Author and article information

                Contributors
                Kaveh Baghaei:
                ORCID: http://orcid.org/0000-0003-2102-9729
                kavehbaghai@gmail.com
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1479-5876
                Publication date (Electronic): 10 May 2022
                Publication date PMC-release: 10 May 2022
                Publication date Collection: 2022
                Volume: 20
                Electronic Location Identifier: 206
                Affiliations
                [1 ]GRID grid.411600.2, Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, , Shahid Beheshti University of Medical Sciences, ; Tehran, Iran
                [2 ]GRID grid.411705.6, ISNI 0000 0001 0166 0922, Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, , Tehran University of Medical Sciences, ; Tehran, Iran
                [3 ]GRID grid.411705.6, ISNI 0000 0001 0166 0922, Cell-Based Therapies Research Center, Digestive Diseases Research Institute, , Tehran University of Medical Sciences, ; Tehran, Iran
                Author information
                http://orcid.org/0000-0003-2102-9729
                Article
                Publisher ID: 3405
                DOI: 10.1186/s12967-022-03405-8
                PMC ID: 9088152
                PubMed ID: 35538576
                SO-VID: 45c58aad-5f47-4a9e-b63b-23e552d3e2ba
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 10 March 2022
                Date accepted : 24 April 2022
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                ScienceOpen disciplines: Medicine
                Keywords: cancer animal model,pdx,preclinical study,humanized model,avatar model of cancer
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: cancer animal model, pdx, preclinical study, humanized model, avatar model of cancer

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