Periodic Reporting for period 1 - DISCERN (Discovering the causes of three poorly understood cancers in Europe)
Reporting period: 2023-01-01 to 2024-06-30
The overall goal of DISCERN is to understand the causes of three poorly understood cancers in Europe; renal, pancreatic and colorectal cancer, and help to explain their geographical distribution, including their high incidence in central and eastern Europe. This will be achieved by combining large-scale European biorepositories comprising population-based cohorts and tumour case-series with state-of-the-art molecular profiling techniques and machine learning approaches. In particular, DISCERN will identify potential new causal risk factors for the three cancers using novel exposomics and proteomics scans, as well detailed geospatial and environmental exposure information from 16 large-scale epidemiological cohorts including almost 900,000 individuals. It will also explore biological mechanisms on how these risk factors are potentially causing these cancer types with a focus on promoting factors in normal tissues using deep sequencing, single cell multi-omics and spatial proteomics. The causal effects of identified cancer risk factors and the cellular signalling responses they trigger will be further evaluated using a panel of stem cells and colon, renal and pancreatic 3D organoids. The results from DISCERN will be disseminated to citizens, patients and policy makers through collaborating patient and participant organizations. DISCERN will provide the critical evidence base required to develop new prevention strategies to tackle the growing burden of renal, pancreatic and colorectal cancer in Europe. This action is part of the Cancer Mission cluster of projects on "Understanding".
In the initial phase, this large, multi-disciplinary project focused on establishing efficient communication across the participating teams and data and information sharing. Key achievements include:
- WP8: Created a Microsoft Teams channel to facilitate consistent and efficient information and document sharing among partners. Launched the DISCERN website for the purpose of increasing external visibility of the project and sharing its objectives and outcomes.
- WP5: Developed a centralised data sharing platform for data storage and access for all partners.
Regarding establishment of the study resources and infrastructure, progress has been made by WP1 in designing the DISCERN case-cohort study for renal, colorectal, and pancreatic cancers. These will be utilised for the internal exposome scans and sample preparations have been finalized. Recruitment for the tumour case series is ongoing in Spain and Italy. Sample selection for proteomic and mass spectrometry analyses has been completed and are awaiting analysis. The selected samples will undergo various molecular analyses.
The overall status of the ongoing work is outlined below:
• In WP2, to characterise the internal chemical exposome, protocols for both GC-MS and LC-MS methods have been established and are ready to be applied for sample analysis. Regarding the external exposome, the EU EXPANSE database and DISCERN cohorts are currently being harmonised to identify potential carcinogenic environmental exposures. In addition, protocols for microbiome analysis have been established and optimised which will be performed on colorectal and pancreatic cancer samples to identify potentially carcinogenic microorganisms.
• WP3 developed a comprehensive pipeline for error-correcting duplex DNA sequencing across various tissues, enabling detailed analysis of clonal structures. A regression-based approach has been designed and tested to link clinical features of donors with variations in clonal structures in normal kidney, colon, and pancreas tissues.
• In WP4, the circulating proteome is currently being characterised in blood samples from the cancer case series using the Olink panels to survey around 1,500 proteins for each cancer site. Specific protein panels have been tailored to each cancer to maximise the number of proteins included in this analysis. Additionally, multiplexed imaging of the tumour microenvironment is being optimised for tissue sections, firstly for renal cancer cases, while the antibody panel selection is finalised, incorporating the output of the aforementioned Olink proteomic analyses.
• In WP5, various omics layers will be leveraged with machine learning algorithms and mendelian randomisation to elucidate causal factors underlying each of these three cancers. Such factors will be confirmed and further characterised using experimental systems in WP6.
• WP6 validated the specificity and reproducibility of various hiPSC reporter lines for assessing cancer-related stress signalling pathways in renal proximal tubule-like cells (PTLCs). These reporter lines include markers for DNA damage, oxidative stress, inflammation, and cell cycle phases. For pancreatic tissue, differentiation protocols for pancreatic organoids were established, and preliminary results showed some activity in response to endogenous factors. Future plans include RNA-seq to explore gene expression changes in response to these factors and testing compounds known to induce cancer.
• WP7 published the "Communication, Dissemination, and Exploitation Plan" (D7.2) outlining strategies for engaging internal and external stakeholders in the DISCERN project. The plan ensures clear communication of project results and disseminating findings to the public via social media. WP7 partners also created a dedicated DISCERN webpage and shared updates through social media with the public, including partners and stakeholders.
- WP8: Created a Microsoft Teams channel to facilitate consistent and efficient information and document sharing among partners. Launched the DISCERN website for the purpose of increasing external visibility of the project and sharing its objectives and outcomes.
- WP5: Developed a centralised data sharing platform for data storage and access for all partners.
Regarding establishment of the study resources and infrastructure, progress has been made by WP1 in designing the DISCERN case-cohort study for renal, colorectal, and pancreatic cancers. These will be utilised for the internal exposome scans and sample preparations have been finalized. Recruitment for the tumour case series is ongoing in Spain and Italy. Sample selection for proteomic and mass spectrometry analyses has been completed and are awaiting analysis. The selected samples will undergo various molecular analyses.
The overall status of the ongoing work is outlined below:
• In WP2, to characterise the internal chemical exposome, protocols for both GC-MS and LC-MS methods have been established and are ready to be applied for sample analysis. Regarding the external exposome, the EU EXPANSE database and DISCERN cohorts are currently being harmonised to identify potential carcinogenic environmental exposures. In addition, protocols for microbiome analysis have been established and optimised which will be performed on colorectal and pancreatic cancer samples to identify potentially carcinogenic microorganisms.
• WP3 developed a comprehensive pipeline for error-correcting duplex DNA sequencing across various tissues, enabling detailed analysis of clonal structures. A regression-based approach has been designed and tested to link clinical features of donors with variations in clonal structures in normal kidney, colon, and pancreas tissues.
• In WP4, the circulating proteome is currently being characterised in blood samples from the cancer case series using the Olink panels to survey around 1,500 proteins for each cancer site. Specific protein panels have been tailored to each cancer to maximise the number of proteins included in this analysis. Additionally, multiplexed imaging of the tumour microenvironment is being optimised for tissue sections, firstly for renal cancer cases, while the antibody panel selection is finalised, incorporating the output of the aforementioned Olink proteomic analyses.
• In WP5, various omics layers will be leveraged with machine learning algorithms and mendelian randomisation to elucidate causal factors underlying each of these three cancers. Such factors will be confirmed and further characterised using experimental systems in WP6.
• WP6 validated the specificity and reproducibility of various hiPSC reporter lines for assessing cancer-related stress signalling pathways in renal proximal tubule-like cells (PTLCs). These reporter lines include markers for DNA damage, oxidative stress, inflammation, and cell cycle phases. For pancreatic tissue, differentiation protocols for pancreatic organoids were established, and preliminary results showed some activity in response to endogenous factors. Future plans include RNA-seq to explore gene expression changes in response to these factors and testing compounds known to induce cancer.
• WP7 published the "Communication, Dissemination, and Exploitation Plan" (D7.2) outlining strategies for engaging internal and external stakeholders in the DISCERN project. The plan ensures clear communication of project results and disseminating findings to the public via social media. WP7 partners also created a dedicated DISCERN webpage and shared updates through social media with the public, including partners and stakeholders.
At 18 months into our 5-year project, it's still early to report outcomes beyond the state of the art. However, foundational work is progressing well, as detailed in the technical report, setting the stage for future advancements.