INFRAFRONTIER Conference 2020

Targeting Cancer with Animal Models

October 7 to 8, 2020      Virtual Conference

Please note: Due to the COVID-19 pandemic, the conference has been rescheduled to 07 - 08 October and moved online completely. This site has been updated accordingly. 

 

 

 

Registration deadline: October 2, 2020

After cardiovascular diseases, cancer is the leading cause of death and one of the major contributors to premature deaths in the EU. In 2016, one quarter (26.0%, 1.3 million people) of the total number of deaths in Europe were due to cancer and it was predicted to kill 1.41 million in 2019. The EC has taken a strong stand in the fight against cancer with the inception of its Europe Beating Cancer Plan and the Cancer Mission area for the Horizon Europe framework beginning in 2021. The Cancer Mission is guided by experts from various facets of cancer treatment like cancer research, innovation, policy, healthcare provision and practice. These experts constitute the Cancer Mission Board. 

With recent biomedical advances it has become obvious that cancer is not a single disease but a collection of several diseases. What these maladies have in common is the uncontrolled growth of cells disrupting the delicate balance between life and death; proliferation and apoptosis. Cancer research and treatment are particularly challenging because tumours exhibit different tumour origins and mechanisms for subverting the natural cellular checkpoints for survival, death, immune evasion, drug sensitivity and metastatic invasion. To further complicate matters, this heterogeneity is also prevalent among cells of the same tumor. Thus, the treatment of cancers requires a more personalised approach customised towards a particular tumours genetic and cellular perturbations. 

Mouse models are used in cancer research to explore the causality between cancer genes and carcinogenesis, and as models to develop and test novel therapies. In addition, they have become ideal models for precise individualized cancer therapy thanks to the advancements in CRISPR/Cas9-mediated genome editing, patient xenograft implantation and microbiota studies enabling them to effectively replicate the aforementioned cancer heterogeneity in a laboratory setting. 

The INFRAFRONTIER Conference 2020 ‘Targeting Cancer with Animal Models’ aims to showcase such innovative animal models used in cancer research and also introduce the Cancer Mission Board to the cancer research community. 

The main objectives of this conference will be to:

  • Present latest research on innovative cancer models
  • Showcase INFRAFRONTIER services for cancer research
  • Align the scientific strategy on cancer mouse models with the Horizon Europe Cancer Mission

 

 Draft Agenda

OCTOBER 7, 2020

SESSION 1 - Innovative in vivo and in vitro Models in Cancer Research

 

13:00 - 13:15Welcome and Introduction 
13:15 - 14:00

Keynote:

tba

Hellmut Augustin

German Cancer Research Centre (DKFZ), Germany

14:00 - 14:20tba

Jos Jonkers

Netherlands Cancer Institute (NKI), Netherlands

14:20 - 14:40tba

Pirjo Laakkonen

Helsinki Insitute of Life Science (HiLIFE), Finland

14:40 - 15:00
Absence of mouse‑driven genomic evolution during engraftment and propagation of patient-derived cancer xenografts

Enzo Medico, University of Torino and Candiolo Cancer Institute, Candiolo, Italy; EurOPDX Consortium.

 

Patient-Derived Xenografts (PDXs) are preclinical models largely used to study tumor biology and drug response. Recent literature highlighted the possibility that growth of human tumours in a mouse microenvironment imposes a selection driving mouse?specific genetic evolution of PDXs, which may compromise their reliability as human cancer models. Conversely, independent studies observed a conservation of the genomic landscape during PDX engraftment and passaging. We resolved these contradicting observations by systematically evaluating copy number alteration (CNA) changes and the genes they affect during engraftment and passaging in a large series of PDX models. CNA data generated and collected by the EurOPDX consortium and the PDXNet Consortium comprised 1548 patient (PT) and PDX datasets (1451 unique samples) from 509 models derived from American, European, and Asian cancer patients, spanning across 16 tumor types. Assessment of CNA changes by pairwise (PT-PDX or PDX-PDX) correlation and residual analysis to control for systematic biases confirmed high retention of the CNA profile during PDX engraftment and passaging.

We further analysed CNA profiles of 87 colorectal and 43 breast cancer triplets, each composed of matched patient’s tumor (PT) and PDX at early (PDX?early) and later (PDX-late) passage. In this way, for each tumor type, we generated three perfectly matched PT, PDX-early and PDX-late cohorts and performed CNA recurrence analysis by GISTIC in each cohort. The hypothesis was that if the mouse host induces a selective pressure capable of shaping the CNA landscape during PDX engraftment and propagation, GISTIC analysis would highlight systematic and progressive changes, from the PT to the PDX-early cohort, and then to the PDX-late cohort. Notably instead, the CNA profiles of the PT and PDX-early/late cohorts were virtually indistinguishable, with no progressive accumulation or loss of CNA during PDX passage and only minor changes not functionally related or associated to cancer-driver or actionable genes. Interestingly, we found that a major contributor to the differences between PDX samples is lineage-specific drift associated with splitting of tumours into fragments during PDX propagation. In summary, our systematic analysis of DNA-based CNA profiles excluded a systematic mouse driven selection via copy number changes, thus supporting the robustness of PDXs as preclinical models for predicting drug response.

Enzo Medico

University Of Turin (UniTO), Italy

15:00 - 15:30Coffee Break 
15:30 - 15:50
Cyclooxygenase 2-driven inflammation in pancreatic cancer

Chiblak, Sara1, Gräbner, Rolf2, Habenicht, Andreas2, Giese, Nathalia3, Büchler, Markus3, Fürstenberger, Gerhardt1, and Müller-Decker, Karin


1German Cancer Research Centre, Heidelberg, Core Facility Tumor Models, Heidelberg,Germany; 2,Friedrich-Schiller-University, Institute for Vascular Medicine, Jena, Germany, 3Ruprecht-Karls- University, Department of Surgery, Heidelberg, Germany. Contact: k.mueller-decker@dkfz.de

 

The cause-effect relationship between over-expression of pro-inflammatory cyclooxygenase (COX)-2, COX-2-mediated prostaglandin (PG) signaling and the development of epithelial cancers is universally accepted. Depending on the cellular context, PG stimulate growth, angiogenesis, and modulate immune functions in inflammation-driven cancers. Keratin 5 promoter-driven COX-2 (K5 COX-2) transgenic mouse lines develop pre-invasive neoplasms in various epithelial tissues including ductal pancreatic neoplasms, which resemble human precursor lesions of pancreatic ductal adenocarcinoma (PDAC), i.e. cystic intra-ductal papillary mucinous neoplasms and pancreatic intra-epithelial neoplasias. These phenotypic changes are associated with pronounced inflammatory infiltrates. Gene expression analysis points to a significant synthesis of TLO (ectopic tertiary lymphoid organs)-relevant cytokines. At the cellular level, in the diseased pancreata diffuse inflammatory infiltrates are observed besides prominent inflammatory clusters. These are comprised of B-cells, T-cells, follicular dendritic cells, macrophages, and high endothelial venules decorated with lymphocyte adhesion molecules, altogether known as hallmarks of TLO, which arise in chronic inflammatory diseases but with a still poorly characterized function. In addition, typical chemokines such as CXCL13, lymphotoxin-beta, and CCL19 are expressed. Such an inflammatory phenotype is suppressed by inhibition of COX-2 activity whereby celebrex-fed transgenics exhibit fewer and smaller clusters, indicating the involvement of COX-2 in the establishment of TLO; a putative novel COX-2-effect on local immunity. Follicular clusters rich in B- cells and T-cells, with vessels that express peripheral lymph node addressin are also observed in COX-2-positive human PDAC. Published clinical data suggest that TLO do not represent a high-risk environment and are associated with a comparably good prognosis in human PDAC.

Karin Müller-Decker

German Cancer Research Centre (DKFZ), Germany

15:50 - 16:10 tba

Mathew Garnett

Wellcome Sanger Institute, United Kingdom

16:10 - 16:30
Development of a human RANKL-driven mouse model of mammary carcinogenesis

Ntari, Lydia1; Christodoulou-Vafeiadou, Eleni1; Kolokotroni, Anthi2; Papanastasiou D, Anastasios3; Rouchota, Maritina4; Loudos, George4; Douni, Eleni2,5, Denis C, Maria1, Karagianni, Niki1

1 Biomedcode Hellas SA, Vari, Greece

2 Insitute of Biodivision, Biomedical Sciences Research Center “Alexander Fleming”, Athens, Greece

3 Department of Biomedical Sciences, University of West Attica, Athens, Greece

4 Bioemission Technology Solutions (BIOEMTECH), Lefkippos Attica Technology Park, NCSR “Demokritos”, Greece

5 Laboratory of Genetics, Department of Biotechnology, Agricultural University of Athens, Athens, Greece

* e-mail: lntari@biomedcode.com

 

Breast cancer is the most frequent and highest lethality-causing cancer among women worldwide, as existing treatments remain inadequate. Therefore, the need to develop new personalized targeted treatments is vital.

 

RANKL(receptor activator of NF-?B ligand) protein and its receptor RANK have been shown to play a significant role in the initiation and development of breast cancer in mice, in addition to their known role in bone homeostasis1, thus offering an attractive therapeutic target of mammary carcinogenesis. In order to study further its role and its therapeutic potential in breast cancer, we induced progesterone-driven carcinogenesis1 in mice that overexpress human RANKL protein together with its mouse counterpart(TghuRANKL)2, as well as mice that explicitly express human RANKL in the absence of functional mouse RANKL(TghuRANKL/RANKLtles/tles)3. Nine-to-fifteen weeks following induction, all mice developed palpable tumours, that were analysed clinically as well as histopathologically. Clinical analysis included in vivo tumour measurements and whole-body imaging, using live positron emission tomography scanning(?-eyeTM,BIOEMTECH). Histopathological analysis included immunohistochemistry as well as evaluation of tumour characteristics in H/E-stained slides. Tumour initiation and development in WT and TghuRANKL mice was ameliorated following treatment with an anti-RANKL inhibitor blocking both mouse and human RANKL, while mammary carcinogenesis was almost completely prevented following treatment with the commercially available anti-huRANKL denosumab.

 

Collectively, we present a human RANKL-driven mouse model of mammary carcinogenesis that can be used as basis for the development of an evaluation tool for huRANKL-targeted therapeutics, as well as for downstream targets of its signalling cascade with a role in breast cancer biology.

Bibliography 1. Schramek et al. Nature (2010), 468:7320 2. Rinotas et al. Journal of Bone and Mineral Research (2014), 29 (5): 1158–1169 3. Douni et al. Human Molecular Genetics (2012), 21:784–98

Lydia Ntari

Biomedcode, Greece

16:30 - 16:50tba 

tba

 

OCTOBER 8, 2020

SESSION 2 - Stakeholder Talks

09:00 - 09:45
Keynote: Investigating cancer immunotherapies using mouse models

Malissen Bernard, Luche Hervé, Malissen Marie and Zarubica Ana Centre d’Immunophénomique, PHENOMIN-CIPHE, Marseille, France

 

The possibility to edit the mouse genome and to profile the immune system of the resulting mouse models has permitted many discoveries in cancer treatment and immunotherapy, including the anti-tumor effects of CTLA-4 and PD-1 blockade. Moreover, mouse models provide the unique possibility to establish causal relationships under in vivo physiological conditions. For instance, it is presently possible to track and ablate in vivo most of the cell types involved in innate and adaptive immunity. This possibility will be exemplified using a subset of dendritic cells that plays a key role in tumor immunity by helping T cells to target tumors. However, some features of human cancer immunobiology are not fully reflected by current mouse models. For instance, the immune system of laboratory mice kept under SPF conditions more closely resembles that of neonatal humans, while co-housing laboratory mice with ‘dirty’ mice ‘humanizes’ their T cell population profiles to mimic that of adult humans. As will be outlined, CIPHE has the ability to develop genetically engineered mouse models under SPF/SOPF conditions including mice with humanized checkpoint molecules and well-characterized syngeneic models. CIPHE can also phenotype their immune system under normal and pathological conditions (inflammation and cancer) using advanced multiparametric flow, mass, and spectral cytometry. To more accurately mimic the complexity of the human tumor microenvironment, CIPHE has acquired the Hu-Mice technology (hemato-lymphoid humanised mice) via a strategic partnership and combines it with its expertise in high-content immunoprofiling to further our knowledge in human immunobiology and oncology.

Bernard Malissen

Centre d’Immunologie Marseille-Luminy (CIML), France

09:45 - 10:05tba

Fabio Mammano

Institute of Biochemistry and Cell Biology (CNR), Italy

10:05 - 10:25

Mapping modifiers for different cancer developments in collaborative cross mice

Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Tel-Aviv, Israel

 

 

A number of genetic modifier loci for different cancers were previously mapped, but so far, most of the underlying genes have not been identified. The Collaboratoive Cross (CC) genetic reference population is, the next generation of mouse genetic reference population, allows time and cost-efficient mapping of target regions as quantitative trait loci (QTLs) that are responsible for the genetic variance of a specific complex trait. The CC is a large panel of recombinant inbred (RI) strains derived from a genetically diverse set of eight founder strains and designed specifically for complex trait analysis and power than any reported approaches. In order to identify modifier genes associated with cancer developments, we performed QTL analysis of cancer development using F1 crosses between mice of different CC lines, and mice carrying mutated suppressor cancer genes including; Adenomatous polyposis coli (APC) for intestinal cancer (IC) development, and Head and Neck Squamous Cell Carcinoma (HNSCC) and breast cancer. Males of C57BL/6Min and C57BL/6Smad4ko lines were crossed with females of different CC lines for developing F1 crosses, for studying IC and HNSCC, respectively. For IC project, F1 offspring were terminated at 23 weeks and polyp counts from three small intestinal and colon were recorded, separately. The number of polyps in all these sub-regions varied significantly between the different F1 crosses. Nine distinct and novel QTL at 90 and 95% genome-wide significant (GWS) thresholds levels, and at least additional 16 more QTL at 50% GWS were mapped. HNSCC and other cancers will be discussed at the conference.

Fuad Iraqi

Tel Aviv University, Sackler Faculty of Medicine, Israel

10:25 - 10:45

A rodent model of KIT-induced human cancer: Clinical and histopathological characterization

Rathkolb, Birgit 1,2,3, Klein-Rodewald, Tanja 1, Kraiger, Markus1, Micklich, Kateryna1, Calzada-Wack, Julia1, Sanz-Moreno, Adrián1, Fuchs, Helmut 1, Gailus-Durner, Valerie 1, Aigner, Bernhard 2, Wolf, Eckhard2, Hrabé de Angelis, Martin 1,3,4

1 Helmholtz Zentrum München, Institute of Experimental Genetics and German Mouse Clinic, Neuherberg, Germany

2 Ludwig-Maximilians-Universität München, Institute of Molecular Animal Breeding and Biotechnology, Munich, Germany

3 Member of the German Center of Diabetes Research, Neuherberg, Germany

4 Technische Universität München, Center of Life and Food Sciences Weihenstephan, Chair of Experimental Genetics, Freising-Weihenstephan, Germany

 

The c-kit gene plays a major role during differentiation and proliferation of several cell types and encodes the receptor tyrosine kinase KIT which mediates signaling of the stem cell factor. Activating KIT-mutations represent one possible primary cause of aggressive types of neoplasias, such as gastrointestinal stromal tumors (GIST), acute myeloid and mast cell leukemia (AML, MCL), melanoma as well as germ cell tumors and are also associated with several other types of cancer. The development of the KIT-specific tyrosine kinase inhibitor Imatinib significantly improved treatment options. However, a group of mutations associated with resistance to Imatinib treatment has been identified.

 

A novel ENU-induced mouse mutant, provisionally named MVD013, carrying the homologous mutation to an Imatinib-resistant mutation found in different types of human cancer in the murine Kit protein, was generated on a C3HeB/FeJ (C3H) genetic background during the Munich ENU Mouse Mutagenesis Project and characterized in the German Mouse Clinic. Heterozygous mutant animals showed initially permanent microcytic polycythemia, followed by age-related changes in differential blood counts, hyperproliferation of gastrointestinal stromal cells associated with disturbed ingesta transport and in females late-onset mammary carcinoma development. Preliminary results from an outcross to C57BL/6J mice indicated that the genetic background (C3B6F1) significantly influences disease course and severity. By longitudinal in-vivo monitoring of disease progression on different genetic backgrounds we aim to identify relevant unknown genetic modifying factors. Here we report on the clinical and pathological characterization of this novel disease model on C3H and C3B6F1 background.

 

References: Lennartsson and Rönnstrand (2012): Stem Cell Factor/ c-Kit: From basic science to clinical implications. Physiol Rev 92: 1619-1649

Hrabe de Angelis et al. (2000): Genome-wide, large-scale production by ENU mutagenesis. Nature Genet. 25(4): 444-447

Aigner, Rathkolb et al. (2011): Generation of N-ethyl-N-nitrosourea-induced mouse mutants with deviations in hematological parameters. Mamm Genome 22: 495-505

Birgit Rathkolb

Helmholtz Center Munich, German Mouse Clinic (GMC), Germany

10:45 - 11:15Coffee Break 
11:15 - 11:35
From the Bytes to the Bedside: The Role of Collagen XVIII in Normal and Malignant Hematopoiesis

Lakkala, Juho a, Kaur, Inderjeeta a, Devarajan, Raman a, Savolainen, Eeva-Riitta b, Heljasvaara, Ritvaa a, Pihlajaniemi, Tainaa a, Izzi, Valerio a,c

 

a Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland

b Dept. of Hematology, Oulu University Hospital, Oulu, Finland

c The Finnish Cancer Institute, Helsinki, Finland

 

The endless combinations of extracellular matrix (ECM) proteins, cytokines, chemokines and growth factors – collectively known as the matrisome – present in the tumor microenvironment play a paramount role in all stages of tumorigenesis. This is also true for acute myeloid leukemia (AML), though in the case of liquid neoplasms the ECM is mostly believed to be produced and modulated by stromal cells.

In our work, we have made use of big data to identify ECM moieties associated with AML progression and chemoresistance and identified Collagen XVIII (Col18a1) as an important gene for disease progression. Generation of mouse lines defective for Col18a1 confirmed these findings, demonstrating that the lack of this collagen triggers a transplantable, CD47-dependent cell-intrinsic myeloproliferative state that aggravates over time and configures as a form of pre-leukemia, which can be reverted by specific recombinant moieties of Col18a1.

These findings open new prognostic possibilities for the management of AML progression and suggest novel molecular interactions worth further exploration for the development of novel therapeutic approaches.

 

Valerio Izzi

University Oulu, Faculty of Biochemistry and Molecular Medicine, Finland

11:35 - 11:55
Predictive modeling, applied to genetically engineered mouse models of breast or lung cancer, provides insights into major oncogenic pathways

The CanPathPro Consortium

Partners:

Banga, Julio1, Frappart, Lucien2, Hasenauer, Jan3, Herault, Yann4, Jonkers, Jos5, Koubi, David6 , Lange, Bodo7, Lines, Glenn8, Ploubidou, Aspasia2, Rinner, Oliver9

1 Spanish National Research Council, CSIC, Spain

2 Leibniz Institute on Aging, Germany

3 Helmholtz Zentrum München GmbH, Germany

4 Institut Clinique de la Souris, France

5 Netherlands Cancer Institute, The Netherlands

6 Finovatis SAS, France

7 Alacris Theranostics GmbH, Germany

8 Simula Research Laboratory AS, Norway

9 Biognosys AG, Switzerland

 

The H2020 project CanPathPro is building and validating a computational predictive modelling platform applied to cancer. To this end, we develop and refine bioinformatic and experimental tools, utilized in generation and evaluation of systems biology modelling predictions.

The presented work employs following technologies and methodologies:

  • biological systems representing 3 levels of biological complexity (genetically engineered mouse models –GEMMs– of breast or lung  cancer, organoids and cell lines derived thereof);                                                                                                                    
  • next generation sequencing and SWATH-based phospho/proteomics;                                                                                      
  • two large-scale computational mechanistic models.

 

The highly-defined biological systems are used (i) to activate selected oncogenic stimuli that modulate pathway components in a systematic manner; (ii) to characterize the signaling changes occurring during cancer development - thus generating temporally resolved datasets for model training; and (iii) to validate, in vitro and in vivo, the modelling predictions.

 

The mechanistic models, based on ordinary differential equations, enable prediction of phenotypes and drug response in mouse or human. Model parameters are defined using project-derived experimental data, either via parameter estimation strategies or via selection of parameter distributions by a Monte Carlo approach.

 

In conclusion this work encompasses a highly integrative systems biology approach generating and validating new hypotheses on cancer pathways signaling and cross-talk identifying new signal flow and suggests new ways to interfere with tumor growth.

Bodo Lange 

Alacris Theranostics, Germany

11:55 - 12:05Twitter Poster Session

 

 

SESSION 3 - European Cancer Research Policy

13:00 - 13:30

Keynote:

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Tomi Mäkelä

Helsinki Insitute of Life Science (HiLIFE), Finland

Member of EU Cancer Mission Board

13:30 - 13:45

INFRAFRONTIER - Rodent models for understanding cancer

Michael Räß

INFRAFRONTIER, Germany

13:45 - 14:00
EurOPDX/EDIReX, a Research Infrastructure that provides access to standardized PDX resources and data in Europe and globally

Massimiliano Borsani1, Emilie Vinolo2

Cancer cell lines used to be the gold standard in preclinical studies, but they show a high failure rate in predicting therapeutic responses in patients. Patient-derived cells and tumours are gaining more attention in cancer modeling, necessary for precision medicine approaches. In particular, Patients-Derived tumour Xenografts (PDXs) are emerging as a promising tool to address clinically relevant questions [1].

Launched in 2013, the EurOPDX Consortium gathers 18 research institutions (www.europdx.eu), with the goal to maximize exploitation of patient-derived models by: (i) integrating institutional collections into a single virtual repository; (ii) defining common standards, thus improving preclinical data reproducibility (FAIR principles, [2]); (iii) sharing models within and outside the consortium to perform collaborative precision oncology “xenopatient” trials.

EurOPDX is now running a 4-year project (EDIReX project, H2020 grant no. 731105) to build a specific distributed Research Infrastructure (RI) to offer access to PDX resources through Trans-National Access calls and web portals, like the new EurOPDX Data Portal (dataportal.europdx.eu) for model selection and data browsing, and a dedicated instance of the cBioPortal (cbioportal.europdx.eu) for model-associated molecular data.

Aims and advantages of a RI for patient-derived models will be discussed.

 

 References

[1] Byrne, A., Alférez, D., Amant, F. et al. Nat Rev Cancer 17, 254–268 (2017).

https://doi.org/10.1038/nrc.2016.140

[2] https://www.go-fair.org/fair-principles/

 

Authors

1 European Institute of Oncology, Milano, Italy.

2 Seeding science SRL, 1342 Limelette, Belgium.

Massimiliano Borsani

EurOPDX, Italy

14:00- 14:15

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14:15 - 14:30

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14:30 - 14:45

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14:45 - 15:30

Panel Discussion

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15:30 - 15:45

Wrap up

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 Registration

Please register here. Registration deadline is October 2, 2020. We will send you a link a few days before the conference takes place. 

Twitter Poster Session

The Online Twitter Poster Session will take place from Oct 7 noon to Oct 8 noon on Twitter. Please tweet your posters at a time most convenient to you, depending on your time zone. All official virtual posters will be retweeted from @InfrafrontierEU. Selected posters will be showcased in Session 2 on Oct 8. Here are the guidelines. Please use this template to make your poster. 

What is an Twitter poster session?

Instead of a conventional poster session wherein the printed poster is displayed, and the author present these posters to an audience at the conference venue, this online poster session will take place on Twitter. The participants will tweet their posters in the form of images accompanied by a brief summary. Please include your contact information (email address, etc.) on the poster slides for further interaction with interested viewers. 

Find the instructional video here.

Please contact info@infrafrontier.eu if you have any questions.