To facilitate the organisation and management, the project is structured in “Work packages” which together comprise the project. CAM-PaC consists of 12 work packages (WPs). Each WP is carried out by a varying number of involved parties. The WP leader supervises and adjusts the process flow and works closely with the project office. The activity of the WP will be overseen by the chair of the working group.
Novel genetically engineered mouse models of pancreatic cancer (Leader: PolyGene / S. Selbert)
- To develop, apply and evaluate reverse erythromycin (rE-Rex)/ pristinamycin (rPip) and phloretin expression system (rPEACE) for the reversible switch on/off of gene expression in vivo.
- To use these novel systems of highly flexible tempero-spatial transgene control to generate GEMM allowing to re-assess and expand knowledge on the roles of known oncogenes and tumour suppressor genes in pancreatic cancer (Kras, p53, p16) in different phases of tumour initiation and progression
- To generate novel GEMM with targeted activation/inactivation of novel PDAC/CSC candidate genes identified in WP2 and WP3
In addition to providing highly relevant information on the functional roles of oncogenes and tumour suppressor genes in various stages (development, maintenance, progression) of pancreatic cancer, WP1 will thus develop efficient and reliable tools and technologies for in vivo phenotyping with broad applicability in many areas of biological or medical research. Generation of a total number of 20 mouse models is envisaged and achievable.
Definition of pancreatic cancer stem cell target genes (Leader: CNIO / C. Heeschen)
- Comprehensively and systematically analyse the functional roles of selected target genes in pancreatic cancer cells in tumour progression and therapy resistance in vitro
- Identify molecular mechanisms and signalling pathways involved in mediating these functional effects within epithelial cancer cells as well as between cancer cells and accessory stromal cells
- Provide and phenotype stably transfected cell lines with inducible knockdown of selected target genes for further functional analyses in vitro and in vivo
Thereby, WP2 will i) contribute to creating a portfolio of new and validated therapeutic targets in PDAC, ii) provide in vitro model systems for large-scale metabolic and molecular phenotyping, iii) provide data and experimental validation for systems biology-based approaches to model mechanisms of tumour progression and therapy resistance of PDAC, which may help to guide personalised medicine, and iv) provide cellular models for clinically relevant situations such as therapy resistance that will serve as the basis for the SME`s in this consortium to develop and promote novel in vitro and in vivo assays of high scientific relevance and significant commercial potential.
Definition of pancreatic cancer stem cell target genes (Leader: CNIO / C. Heeschen)
- To comprehensively analyse genes that mediate pancreatic CSC-specific phenotypes (self-renewal, invasiveness, metabolism, tumourigenicity) in vitro and in vivo
- To dissect the role of candidate genes in pancreatic cancer, at the transcriptional and metabolomic level, by modulating target gene expression with RNA interference and subsequently modelling transcriptome and metabolomic alterations
- To determine the role that target genes play in pancreatic cancer initiation and development by selectively controlling their expression in vivo using transgenic mice with hormone regulatable promoters
Therefore, this WP will i) generate data sets for elucidating the function of genes and gene products in pancreatic cancer, ii) integrate data-dense information from the different omics platforms and iii) help develop and validate new animal and in vitro systems for the development of new therapies for pancreatic cancer, specifically targeting CSC, and iv) provide relevant experimental data for SME`s in this consortium to develop and promote novel in vitro and in vivo assays of scientific relevance and commercial potential, v) to contribute HT-omics data on CSC which are mediators of therapy resistance for modelling of predictive subgroups to guide future personalised treatment approaches.
Visualisation of tumour progression, therapy response and resistance phenotyping in GEMM (Leader: TUM-MED / J. Siveke)
- Investigate the sensitivity and robustness of individual parameters from multimodal imaging for detection and progression of defined GEMMs with multiple gene alterations
- Establish non-invasive parameters for assessment of tumour heterogeneity and therapy response
- Apply multi-modal non-invasive imaging for characterisation and monitoring of cancer biology in novel GEMM from WP1 with focus on assessing the role of key genes and signalling pathways in tumour maintenance and progression
With the work performed in WP04, we will thus develop and apply cutting-edge technologies for phenotyping of novel in vivo model systems and vitally contribute to creating a portfolio of new and validated therapeutic targets in pancreatic cancer. Data on cancer biology and therapy response as well as HT-profiling data will contribute to the generation of predictive models in WP10 that in the future may guide personalised medicine approaches for PDAC. The participating SME will benefit from the validation of their in vivo models on a sophisticated imaging platform, usually not accessible to SMEs.
High throughput culturing techniques for pancreatic cancer cells and CSCs (Leader: IBA / K. Lemke)
- To adapt the previously established protocols to the specific cultivation requirements of pancreatic cancer cells and CSCs including the co-culture with stromal cells as a novel cell-based model system
- To functionally analyse genetic changes as well as therapeutic treatments in cellular model systems of pancreatic cancer
- To establish an experimental setup for laboratory experiments and downstream analytical procedures based on atomized cell culturing technology
Thereby WP5 will develop a novel in vitro cell-based model system for the efficient and standardised analysis of cellular phenotypes, with broad applicability for cancer (stem) cell research.
Xenograft models for in vivo validation of candidate gene function (Leader: EPO / D. Behrens)
- To establish a "xeno-factory" of comprehensively characterised primary PDAC-derived mouse xenograft models for preclinical therapeutic trials
- To provide a central platform for in vivo testing of tumourigenicity and chemo resistance of PDAC and CSC cell lines with altered expression of selected target genes
WP6 will thus i) contribute to the development of validated animal and cellular model systems supporting the development of new predictive, preventive or therapeutic approaches, ii) assist in creating a portfolio of new and validated therapeutic targets, iii) enable large-scale metabolic and molecular phenotyping of in vivo model systems, and iv) contribute to developing efficient, standardised and reliable operating procedures for in vivo phenotyping.
Histopathologic and molecular characterisation of human primary tissues and model systems (Leader: UNIVR / A. Scarpa & R. Lawlor)
- Histopathological and molecular characterisation of primary cancers and human-derived mouse xenografts collected and propagated at different sites of the consortium for standardisation and quality control
- Histopathological and molecular classification of neoplastic and preneoplastic lesions of novel transgenic murine models
- The creation of a central biobank and clinical database for testing and validation
Thereby, WP7 will contribute to create a portfolio of samples completely characterised by expert pancreatic pathologists of i) primary PDAC; ii) human derived mouse xenografts; iii) novel transgenic murine models. By applying the same histopathological and molecular characterisation programme to xenografts available and collected at different sites in CAM-PaC, WP07 will be of central importance for the standardisation and harmonisation of protocols and models across the CAM-PaC project. It will also contribute to the creation of a coordinated and harmonised biobank of these samples for use in other workpackages for testing and validation, together with anonymised clinical and prognostic patient data that will be required for predictive modelling in WP10. This will provide the technology oriented SME involved in WP1 & WP6 with access to a sophisticated pancreatic pathology platform and expertise for the validation of PDAC animal models that is usually not available at SMEs.
Large scale metabolic profiling of in vitro and in vivo models of pancreatic cancer (Leader: MPS / T. Hankemeier)
- Customising and miniaturising of available metabolomics platforms for in vivo and in vitro pancreatic cancer samples of CAM-PaC
- Defining the metabolic phenotype of human pancreatic cancer
- Identifying key metabolic pathways in in vitro and in vivo pancreatic cancer models
- Validating key metabolic pathways of pancreatic cancer to identify new possible drug targets
MPS will benefit from participation in CAM-PaC by expanding the company’s portofolio of experimental models and technologies for metabolomic analyses of pancreatic cancer cells and cancer stem cells, which will include the establishment of novel methods and SOPs as well as miniaturisation approaches.
Large scale transcriptomic profiling of in vitro and in vivo models of pancreatic cancer (Leader: CeGaT / S. Biskup)
- Comprehensive profiling of global mRNA and miRNA expression with concomitant mutation analysis of coding sequences using established state of the art next-generation-sequencing
- Development of novel methods for genomic and transcriptome analyses of very limited sample material
- Generation of analytical RNA-Panel that specifically captures genes identified relevant for pancreatic cancer cell therapy response in objectives 2 and 3
By providing large-scale molecular phenotyping of model organisms and in vitro model systems, WP09 will thus i) use generate data for elucidating the function of genes and gene products in biological processes relevant for tumour progression and therapy resistance, and ii) contribute to developing efficient, standardised and reliable tools and standardised operating procedures for molecular phenotyping in many research contexts which will expand the company’s portfolio and generate new market opportunities.
Data integration and pathway modelling (Leader: UULM / H. Kestler)
- Comprehensively integrate the data from the consortium and provide a central storage and knowledge base for the project
- Identify static dependencies and involved pathways on the basis of experimental results from WPs 2, 3, 4, 6, 7, 8 and 9 as well as publicly available data
- Capture the experimental results in static and dynamic mathematical models and give directions for new wet-lab experiments on the basis of model simulations
Thereby, WP10 will i) provide the platform for data integration and exchange to the project partners (https://systardb.informatik.uni-ulm.de/campac-db/login.php), ii) contribute to the identification of new and validated therapeutic targets in PDAC in collaboration with the partners, and iii) provide in-silico models for mechanisms of tumour progression and therapy resistance of PDAC.
Dissemination (Leader: UniMar / T. Gress & M. Buchholz)
- Make CAM-PaC known to the scientific community and the public
- Disseminate the results to the scientific community in the academic, healthcare and pharmaceutical sectors and foster interaction and exchange with the scientific community and the public
- Identify and valorise the intellectual property rights (IPR) generated in CAM-PaC
- Explore possibilities to conduct clinical trials to overcome therapy resistance in pancreatic cancer
Project Management (Leader: UniMar / T. Gress & M. Buchholz)
- Make CAM-PaC achieve its objectives and to deliver in time, budget and quality its milestones and deliverables
- Help the consortium abide by the regulations and contractual obligations according to the grant agreement, its annexes and the consortium agreement
- Look after the project`s finances and to report them properly to the European Commission
- Establish a communication infrastructure which enables the partners to communicate efficiently and to stay connected for the run-time of the project
- Preserve the rights of the partners regarding intellectual property and to act as a mediator in case of disputes