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Genetically Engineered Mice to Study Cancer
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Genetically Engineered Mice to Study Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 40425

Special Issue Editor

Dr. Christian Veltkamp

E-Mail Website
Guest Editor
Division of Translational Cancer Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Partner Site Munich, Institute of Translational Cancer Research and Experimental Cancer Therapy, Klinikum rechts der Isar, TU München, München, Germany
Interests: cell Signaling; pancreatic cancer; tumor evolution; resistance; mouse models

Special Issue Information

Dear Colleagues,

Cancer is a group of life-threatening diseases affecting several millions of people globally. In recent years, therapeutic options have been discovered for subsets of specific cancer entities. However, cancer remains still incompletely understood due to the complexity of signaling cascades, the cross-talk between tumor cells and stromal cells as well as metabolic and environmental factors. Genetically engineered mouse models (GEMMs) represent a powerful tool to study cancer biology, as they recapitulate human carcinogenesis by the formation of precursor lesions, invasive cancers, and metastasis. GEMMs enable the roles of specific genetic alterations to be dissected in a tissue-specific manner. Inducible mouse models can mimic therapeutic interventions for the validation of potential targets for cancer therapy.

This Special Issue discusses insights learned from GEMMs about the biology of distinct tumor entities. Furthermore, we provide an overview of new advances in the development and application of GEMMs. This covers innovative approaches to generate somatic genome-engineered mice by CRISPR/Cas9 technology to elucidate functional networks by transposon screening or to perform lineage tracing of cellular subsets. Finally, the use of large animal cancer models, i.e. transgenic pig models, is addressed. Such models help us to study aspects of cancer more closely related to the human situation, such as nutritional influences on cancer development as well as diagnostic measurements. Thus, we provide an overview of how the generation and analysis of advanced mouse models will result in a deeper understanding of cancer with the major goal to translate findings into the clinic.

Dr. Christian Veltkamp
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mouse models
  • cancer
  • GEMMs
  • CRISPR/Cas9
  • Cre/loxP
  • knock-out mouse
  • transgenic mouse
  • somatic genome engineering
  • lineage tracing
  • signaling
  • oncogene
  • tumor suppressor gene
  • gene targeting
  • cell of origin

Published Papers (7 papers)

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Research

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19 pages, 2409 KiB  
Article
Establishment and Characterization of a Brca1−/−, p53−/− Mouse Mammary Tumor Cell Line
by Lilla Hámori, Gyöngyi Kudlik, Kornélia Szebényi, Nóra Kucsma, Bálint Szeder, Ádám Póti, Ferenc Uher, György Várady, Dávid Szüts, József Tóvári, András Füredi and Gergely Szakács
Int. J. Mol. Sci. 2020, 21(4), 1185; https://doi.org/10.3390/ijms21041185 - 11 Feb 2020
Cited by 11 | Viewed by 4864
Abstract
Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. By the age of 80, the estimated risk for breast cancer for women with germline BRCA1 or BRCA2 mutations is around 80%. Genetically engineered BRCA1-deficient mouse [...] Read more.
Breast cancer is the most commonly occurring cancer in women and the second most common cancer overall. By the age of 80, the estimated risk for breast cancer for women with germline BRCA1 or BRCA2 mutations is around 80%. Genetically engineered BRCA1-deficient mouse models offer a unique opportunity to study the pathogenesis and therapy of triple negative breast cancer. Here we present a newly established Brca1−/−, p53−/− mouse mammary tumor cell line, designated as CST. CST shows prominent features of BRCA1-mutated triple-negative breast cancers including increased motility, high proliferation rate, genome instability and sensitivity to platinum chemotherapy and PARP inhibitors (olaparib, veliparib, rucaparib and talazoparib). Genomic instability of CST cells was confirmed by whole genome sequencing, which also revealed the presence of COSMIC (Catalogue of Somatic Mutations in Cancer) mutation signatures 3 and 8 associated with homologous recombination (HR) deficiency. In vitro sensitivity of CST cells was tested against 11 chemotherapy agents. Tumors derived from orthotopically injected CST-mCherry cells in FVB-GFP mice showed sensitivity to cisplatin, providing a new model to study the cooperation of BRCA1-KO, mCherry-positive tumor cells and the GFP-expressing stromal compartment in therapy resistance and metastasis formation. In summary, we have established CST cells as a new model recapitulating major characteristics of BRCA1-negative breast cancers. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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13 pages, 3793 KiB  
Communication
IBTK Haploinsufficiency Affects the Tumor Microenvironment of Myc-Driven Lymphoma in E-myc Mice
by Eleonora Vecchio, Giuseppe Fiume, Chiara Mignogna, Enrico Iaccino, Selena Mimmi, Domenico Maisano, Francesco Trapasso and Ileana Quinto
Int. J. Mol. Sci. 2020, 21(3), 885; https://doi.org/10.3390/ijms21030885 - 30 Jan 2020
Cited by 6 | Viewed by 2595
Abstract
The tumor microenvironment is a dynamic and interactive supporting network of various components, including blood vessels, cytokines, chemokines, and immune cells, which sustain the tumor cell’s survival and growth. Murine models of lymphoma are useful to study tumor biology, the microenvironment, and mechanisms [...] Read more.
The tumor microenvironment is a dynamic and interactive supporting network of various components, including blood vessels, cytokines, chemokines, and immune cells, which sustain the tumor cell’s survival and growth. Murine models of lymphoma are useful to study tumor biology, the microenvironment, and mechanisms of response to therapy. Lymphomas are heterogeneous hematologic malignancies, and the complex microenvironment from which they arise and their multifaceted genetic basis represents a challenge for the generation and use of an appropriate murine model. So, it is important to choose the correct methodology. Recently, we supported the first evidence on the pro-oncogenic action of IBTK in Myc-driven B cell lymphomagenesis in mice, inhibiting apoptosis in the pre-cancerous stage. We used the transgenic Eμ-myc mouse model of non-Hodgkin’s lymphoma and Ibtk hemizygous mice to evaluate the tumor development of Myc-driven lymphoma. Here, we report that the allelic loss of Ibtk alters the immunophenotype of Myc-driven B cell lymphomas, increasing the rate of pre-B cells and affecting the tumor microenvironment in Eμ-myc mice. In particular, we observed enhanced tumor angiogenesis, increasing pro-angiogenic and lymphangiogenic factors, such as VEGF, MMP-9, CCL2, and VEGFD, and a significant recruitment of tumor-associated macrophages in lymphomas of Ibtk+/- Eμ-myc compared to Ibtk+/+ Eμ-myc mice. In summary, these results indicate that IBTK haploinsufficiency promotes Myc tumor development by modifying the tumor microenvironment. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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7 pages, 1496 KiB  
Communication
Evaluating the Combination of Radioimmunotherapy and Immunotherapy in a Melanoma Mouse Model
by R. Jiao, K.J.H. Allen, M.E. Malo, D. Rickles and E. Dadachova
Int. J. Mol. Sci. 2020, 21(3), 773; https://doi.org/10.3390/ijms21030773 - 24 Jan 2020
Cited by 19 | Viewed by 3620
Abstract
Immunotherapy has changed the oncology landscape during the last decade and become standard of care for several cancers. The combinations of immunotherapy with other treatment modalities are also being investigated. One of the challenges to investigate such combinations is to identify suitable mouse [...] Read more.
Immunotherapy has changed the oncology landscape during the last decade and become standard of care for several cancers. The combinations of immunotherapy with other treatment modalities are also being investigated. One of the challenges to investigate such combinations is to identify suitable mouse models for the pre-clinical experiments. In the past, we and other researchers showed that murine B16-F10 melanoma in C57Bl6 mice is refractory to treatment with immune checkpoint inhibitors. In this work we studied the suitability of an alternative syngeneic model, Cloudman S91 murine melanoma in DBA/2 mouse (DBA/2NCrl), to study the combination of immunotherapy targeting PD-1 and radioimmunotherapy targeting melanin. DBA/2 male and female mice were injected subcutaneously with 3–6 million Cloudman S91 cells. When the tumors reached ~150 mm3 volume, the animals were treated intraperitoneally with PBS (sham), h8C3 unlabeled (cold) antibody to melanin, immunotherapy with anti-PD-1 antibody, radioimmunotherapy with 213Bismuth (213Bi)-labeled h8C3 antibody, or several combinations of immunotherapy and radioimmunotherapy. Treatments with immunotherapy alone produced very modest effect on the tumor size, while combination therapy resulted in significant slowing down of the tumor growth, increased animal survival, and no decrease in animal body weight. We conclude that Cloudman S91 murine melanoma in DBA/2 mouse is a suitable model to evaluate combination of immunotherapy of melanoma with tangentially targeted treatments. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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Review

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15 pages, 788 KiB  
Review
Modelling Epithelial Ovarian Cancer in Mice: Classical and Emerging Approaches
by Razia Zakarya, Viive M. Howell and Emily K. Colvin
Int. J. Mol. Sci. 2020, 21(13), 4806; https://doi.org/10.3390/ijms21134806 - 07 Jul 2020
Cited by 11 | Viewed by 4232
Abstract
High-grade serous epithelial ovarian cancer (HGSC) is the most aggressive subtype of epithelial ovarian cancer. The identification of germline and somatic mutations along with genomic information unveiled by The Cancer Genome Atlas (TCGA) and other studies has laid the foundation for establishing preclinical [...] Read more.
High-grade serous epithelial ovarian cancer (HGSC) is the most aggressive subtype of epithelial ovarian cancer. The identification of germline and somatic mutations along with genomic information unveiled by The Cancer Genome Atlas (TCGA) and other studies has laid the foundation for establishing preclinical models with high fidelity to the molecular features of HGSC. Notwithstanding such progress, the field of HGSC research still lacks a model that is both robust and widely accessible. In this review, we discuss the recent advancements and utility of HGSC genetically engineered mouse models (GEMMs) to date. Further analysis and critique on alternative approaches to modelling HGSC considers technological advancements in somatic gene editing and modelling prototypic organs, capable of tumorigenesis, on a chip. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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15 pages, 863 KiB  
Review
Mouse Tumor Models for Advanced Cancer Immunotherapy
by Daria S. Chulpanova, Kristina V. Kitaeva, Catrin S. Rutland, Albert A. Rizvanov and Valeriya V. Solovyeva
Int. J. Mol. Sci. 2020, 21(11), 4118; https://doi.org/10.3390/ijms21114118 - 09 Jun 2020
Cited by 59 | Viewed by 12226
Abstract
Recent advances in the development of new methods of cancer immunotherapy require the production of complex cancer animal models that reliably reflect the complexity of the tumor and its microenvironment. Mice are good animals to create tumor models because they are low cost, [...] Read more.
Recent advances in the development of new methods of cancer immunotherapy require the production of complex cancer animal models that reliably reflect the complexity of the tumor and its microenvironment. Mice are good animals to create tumor models because they are low cost, have a short reproductive cycle, exhibit high tumor growth rates, and can be easily genetically modified. However, the obvious problem of these models is the high failure rate observed in human clinical trials after promising results obtained in mouse models. In order to increase the reliability of the results obtained in mice, the tumor model should reflect the heterogeneity of the tumor, contain components of the tumor microenvironment, in particular immune cells, to which the action of immunotherapeutic drugs are directed. This review discusses the current immunocompetent and immunocompromised mouse models of human tumors that are used to evaluate the effectiveness of immunotherapeutic agents, in particular chimeric antigen receptor (CAR) T-cells and immune checkpoint inhibitors. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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19 pages, 1252 KiB  
Review
Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities
by Pauline J. Beckmann and David A. Largaespada
Int. J. Mol. Sci. 2020, 21(3), 1172; https://doi.org/10.3390/ijms21031172 - 10 Feb 2020
Cited by 13 | Viewed by 5284
Abstract
Transposon mutagenesis has been used to model many types of human cancer in mice, leading to the discovery of novel cancer genes and insights into the mechanism of tumorigenesis. For this review, we identified over twenty types of human cancer that have been [...] Read more.
Transposon mutagenesis has been used to model many types of human cancer in mice, leading to the discovery of novel cancer genes and insights into the mechanism of tumorigenesis. For this review, we identified over twenty types of human cancer that have been modeled in the mouse using Sleeping Beauty and piggyBac transposon insertion mutagenesis. We examine several specific biological insights that have been gained and describe opportunities for continued research. Specifically, we review studies with a focus on understanding metastasis, therapy resistance, and tumor cell of origin. Additionally, we propose further uses of transposon-based models to identify rarely mutated driver genes across many cancers, understand additional mechanisms of drug resistance and metastasis, and define personalized therapies for cancer patients with obesity as a comorbidity. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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21 pages, 1410 KiB  
Review
Genetically Engineered Pigs to Study Cancer
by Daniela Kalla, Alexander Kind and Angelika Schnieke
Int. J. Mol. Sci. 2020, 21(2), 488; https://doi.org/10.3390/ijms21020488 - 13 Jan 2020
Cited by 28 | Viewed by 6908
Abstract
Recent decades have seen groundbreaking advances in cancer research. Genetically engineered animal models, mainly in mice, have contributed to a better understanding of the underlying mechanisms involved in cancer. However, mice are not ideal for translating basic research into studies closer to the [...] Read more.
Recent decades have seen groundbreaking advances in cancer research. Genetically engineered animal models, mainly in mice, have contributed to a better understanding of the underlying mechanisms involved in cancer. However, mice are not ideal for translating basic research into studies closer to the clinic. There is a need for complementary information provided by non-rodent species. Pigs are well suited for translational biomedical research as they share many similarities with humans such as body and organ size, aspects of anatomy, physiology and pathophysiology and can provide valuable means of developing and testing novel diagnostic and therapeutic procedures. Porcine oncology is a new field, but it is clear that replication of key oncogenic mutation in pigs can usefully mimic several human cancers. This review briefly outlines the technology used to generate genetically modified pigs, provides an overview of existing cancer models, their applications and how the field may develop in the near future. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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