Final Report Summary - BONE-NET (European Training Network on Cancer-Induced Bone Diseases)
BONE-NET is a European consortium with complementary expertise in the fields of cancer and bone. It brings together 7 leading academic groups (Université Claude Bernard-UCBL, University of Eastern Finland-UEF, Leiden University Medical Centre-LUMC, University of Liège-ULG, University of Nantes-UNA, Universitätsklinikum Hamburg-Eppendorf-UKE and University of Sheffield-UOS) and 2 SMEs (ServiceXS-SXS and PerkinElmer (asso.)). BONE-NET’s primary objective is to train 10 early-stage (ESR) and 4 experienced (ER) researchers in technical skills such as genomics, proteomics, advance microscopical methods, animal experimentation, noninvasive in vivo imaging methodologies and drug development. The BONE-NET scientific goals can be summarised as follows:
• Investigate early molecular mechanisms associated with metastases in breast and prostate cancers and primary bone cancers
• Identify genes and their regulators that draw cancer cells to colonize bone and let these cells adapt in the bone microenvironment
• Develop new molecularly-targeted therapies and identify novel markers for diagnosis
1.2. Work performed since the beginning of the project and main results
Main activities over the past two years focused on initiating experimental work, recruiting fellows and organizing first joint training events.
Networking
BONE-NET project builds on both previous successful European projects (METABRE and PROMET) and existing collaborations among project partners (“Bisphosphonate Network”). Moreover, communication flow among beneficiaries is also guaranteed thanks to the internal communication platform and the secondments planned in Annex I. Secondments will start on January 2013.
Management
On the management side, the consortium organised and executed the kick-off and three Supervisory Board meetings, set up the internal management processes and recruitment strategy, finalised and signed the Consortium Agreement as well as published the BONE-NET web site. In this period, and due to internal reorganisations, three partners left the network and new entities joined the consortium with a starting date on 01/09/2012: UKE, UOS, SXS. An amendment request was submitted to EC and accepted.
Scientific
BONE-NET project is structured into four RTD/training workpackages. Key findings for each WP are listed below:
WP1 - mRNA and microRNA profiling, M1 to M31
Samples from patients with osteosarcoma and bone marrow aspirates from patients with prostate or breast cancer were collected by UNA, LUMC and UCBL. Animal model samples were also collected as originally scheduled. Consortium agreed on protocols of RNA extraction. Laser microdissection experiments on both human and animal specimens and transcriptomic analyses of miRNAs on animal models are in progress.
WP2 - Proteomic profiling, M2 to M33
A list of miRNAs of interest identified from pre-clinical models of bone metastases and osteosarcoma is now available. UCBL and LUMC have generated mRNA and miRNA expression profiles of osteotropic human breast and prostate cell lines in vitro. Additionally, LUMC has profiled/sequenced chimaeric RNA samples of experimentally-induced bone metastasis. In collaboration with LUMC, UCBL done profiling of microRNAs involved in the epithelial-mesenchymal transition using murine breast cancer cell lines. UCBL also performed profiling of target genes from these microRNAs. Moreover, ULG identified 3 proteins of interest and checked for the expression of these proteins on osteotropic prostate and breast cancer clones from LUMC and UCBL.
WP3 - in-vitro and in-vivo functional analyses, M6 to M39
Stable transduction of osteosarcoma, breast and prostate cancer cells is ongoing at UNA, LUMC and UCBL. Using different cell-based assays, selection and characterization of clones are in progress at UNA, LUMC, UCBL and ULG. In vitro assays will allow partners to determine ability of miRNAs to modulate stemness, clonogenicity and epithelial plasticity. In parallel, UNA, LUMC, UCBL and ULG are setting up in vivo animal models of tumorigenesis and metastasis of human osteosarcoma and breast and prostate cancer. Bone histomorphometric analyses are used to analyse the consequences of skeletal lesions caused by osteosarcoma and carcinomas.
WP4 - Development of novel pharmacological therapies, M24 to M48
Preliminary work in this WP started at UEF (liposome encapsulation of drugs at small and large laboratory scales), UNA (new therapeutic approaches for bone sarcoma) and UCBL (in vivo analyses of blocking gene expression).
Training
The recruitment procedure was agreed during the first Supervisory Board meeting and all open positions were published on BONE-NET and the EURAXESS sites. In the current period, 10 ESR and 1 ER joined the BONE-NET project. The procedure to find suitable candidates to fulfil ER open positions at, SXS, UNA and UCBL was also launched.
In the M1 to M24 period 2 joint training events took place and one was organised:
• Training courses on proteomics and functional genomics (ULG, January 2012).
• Workshop on gene identification and gene therapy (UNA, June 2012).
• Development of Novel Pharmacological Therapies (UEF, February 2013).
1.3. Expected final results and their potential impact and use
The network will identify specific genes and their regulators (microRNAs) that are mediating early events of metastases associated with breast and prostate cancers and primary bone cancers (e.g. osteosarcomas). Every real improvement in healthcare system has by definition a positive impact within the social sphere. Therefore the impact of the BONE-NET programme may be considerable in that we will try and identify patients with cancer who are at higher risk of relapse and, second, we will investigate the effect of new molecularly-oriented therapies targeting micrometastases. The ability to detect micrometastasis and, consequently, predict outcome and, ultimately, to treat adequately patients will undoubtedly decrease morbidity and mortality and therefore reduce the costs on the healthcare system. Moreover, although this project is focusing on primary bone cancers and metastatic breast and prostate cancers, some of the project data will also be relevant and transferable to metastatic disease derived from other cancers where similar molecular mechanisms may occur.
Additionally, upon completion of this project, we anticipate the training programme will have facilitated the transfer of technical skills from one lab to another and the different methodologies shared by the different labs will be therefore harmonized, thereby increasing the international competitiveness of participating institutions.
Coordinator contact: Dr. Philippe Clézardin (philippe.clezardin@inserm.fr)
Project public web site: http://www.bonenet.eu/
• Investigate early molecular mechanisms associated with metastases in breast and prostate cancers and primary bone cancers
• Identify genes and their regulators that draw cancer cells to colonize bone and let these cells adapt in the bone microenvironment
• Develop new molecularly-targeted therapies and identify novel markers for diagnosis
1.2. Work performed since the beginning of the project and main results
Main activities over the past two years focused on initiating experimental work, recruiting fellows and organizing first joint training events.
Networking
BONE-NET project builds on both previous successful European projects (METABRE and PROMET) and existing collaborations among project partners (“Bisphosphonate Network”). Moreover, communication flow among beneficiaries is also guaranteed thanks to the internal communication platform and the secondments planned in Annex I. Secondments will start on January 2013.
Management
On the management side, the consortium organised and executed the kick-off and three Supervisory Board meetings, set up the internal management processes and recruitment strategy, finalised and signed the Consortium Agreement as well as published the BONE-NET web site. In this period, and due to internal reorganisations, three partners left the network and new entities joined the consortium with a starting date on 01/09/2012: UKE, UOS, SXS. An amendment request was submitted to EC and accepted.
Scientific
BONE-NET project is structured into four RTD/training workpackages. Key findings for each WP are listed below:
WP1 - mRNA and microRNA profiling, M1 to M31
Samples from patients with osteosarcoma and bone marrow aspirates from patients with prostate or breast cancer were collected by UNA, LUMC and UCBL. Animal model samples were also collected as originally scheduled. Consortium agreed on protocols of RNA extraction. Laser microdissection experiments on both human and animal specimens and transcriptomic analyses of miRNAs on animal models are in progress.
WP2 - Proteomic profiling, M2 to M33
A list of miRNAs of interest identified from pre-clinical models of bone metastases and osteosarcoma is now available. UCBL and LUMC have generated mRNA and miRNA expression profiles of osteotropic human breast and prostate cell lines in vitro. Additionally, LUMC has profiled/sequenced chimaeric RNA samples of experimentally-induced bone metastasis. In collaboration with LUMC, UCBL done profiling of microRNAs involved in the epithelial-mesenchymal transition using murine breast cancer cell lines. UCBL also performed profiling of target genes from these microRNAs. Moreover, ULG identified 3 proteins of interest and checked for the expression of these proteins on osteotropic prostate and breast cancer clones from LUMC and UCBL.
WP3 - in-vitro and in-vivo functional analyses, M6 to M39
Stable transduction of osteosarcoma, breast and prostate cancer cells is ongoing at UNA, LUMC and UCBL. Using different cell-based assays, selection and characterization of clones are in progress at UNA, LUMC, UCBL and ULG. In vitro assays will allow partners to determine ability of miRNAs to modulate stemness, clonogenicity and epithelial plasticity. In parallel, UNA, LUMC, UCBL and ULG are setting up in vivo animal models of tumorigenesis and metastasis of human osteosarcoma and breast and prostate cancer. Bone histomorphometric analyses are used to analyse the consequences of skeletal lesions caused by osteosarcoma and carcinomas.
WP4 - Development of novel pharmacological therapies, M24 to M48
Preliminary work in this WP started at UEF (liposome encapsulation of drugs at small and large laboratory scales), UNA (new therapeutic approaches for bone sarcoma) and UCBL (in vivo analyses of blocking gene expression).
Training
The recruitment procedure was agreed during the first Supervisory Board meeting and all open positions were published on BONE-NET and the EURAXESS sites. In the current period, 10 ESR and 1 ER joined the BONE-NET project. The procedure to find suitable candidates to fulfil ER open positions at, SXS, UNA and UCBL was also launched.
In the M1 to M24 period 2 joint training events took place and one was organised:
• Training courses on proteomics and functional genomics (ULG, January 2012).
• Workshop on gene identification and gene therapy (UNA, June 2012).
• Development of Novel Pharmacological Therapies (UEF, February 2013).
1.3. Expected final results and their potential impact and use
The network will identify specific genes and their regulators (microRNAs) that are mediating early events of metastases associated with breast and prostate cancers and primary bone cancers (e.g. osteosarcomas). Every real improvement in healthcare system has by definition a positive impact within the social sphere. Therefore the impact of the BONE-NET programme may be considerable in that we will try and identify patients with cancer who are at higher risk of relapse and, second, we will investigate the effect of new molecularly-oriented therapies targeting micrometastases. The ability to detect micrometastasis and, consequently, predict outcome and, ultimately, to treat adequately patients will undoubtedly decrease morbidity and mortality and therefore reduce the costs on the healthcare system. Moreover, although this project is focusing on primary bone cancers and metastatic breast and prostate cancers, some of the project data will also be relevant and transferable to metastatic disease derived from other cancers where similar molecular mechanisms may occur.
Additionally, upon completion of this project, we anticipate the training programme will have facilitated the transfer of technical skills from one lab to another and the different methodologies shared by the different labs will be therefore harmonized, thereby increasing the international competitiveness of participating institutions.
Coordinator contact: Dr. Philippe Clézardin (philippe.clezardin@inserm.fr)
Project public web site: http://www.bonenet.eu/