Project description
Mutation acquisition order in malignant transformation
Despite the use of proofreading and damage repair mechanisms, DNA replication is subject to errors, with cells accumulating mutations over time. However, what triggers cancer formation remains unknown. The ERC-funded SUCCESSion project is working on the hypothesis that the transformation of mutant clones into cancer cells is dictated by the order of mutation acquisition rather than the combination of mutations. Researchers will develop a gene-editing technology that introduces mutations in a sequential order and study their effects on cell behaviour. By focusing on the mammary gland, the study will also examine the impact of these mutations in the tumour microenvironment. Project findings will improve our understanding of tumour initiation and improve cancer risk prediction.
Objective
Mutant cells are abundant in normal tissues, but only very few will transform into life-threatening cancer. The triggers for these mutant clones to transform are unclear. Phylogenetic studies of solid cancers hinted towards an impact of the order of mutation acquisition on the malignant potential of mutant clones. However, to date, no functional studies exist validating these findings in the in vivo context.
Mutant clones closely interact with their environment. Intravital microscopy experiments from my lab showed that phenotypically normal, but mutant clones in the mammary epithelium, the tissue of origin of breast cancer, dynamically rewire their environment in a mutation-specific manner. Hence, I hypothesize that the transforming potential of a mutant clone does not lie in the combination of mutations, but rather in the order in which these mutations were acquired, and thus the way in which the environment of the mutant clone was sequentially rewired, leading to a permissive or a resistant environment for tumour initiation.
Tools to study sequential acquisition of mutations in vivo do not exist. Therefore, the possibility that one mutation may need to precede the other for a mutant clone to transform, has not been studied. SUCCESSion will fill this gap and develop a novel sequential somatic gene editing technology. This will be combined with intravital imaging and transcriptional profiling to study for the first time the effects of different sequences of mutations on cell behaviour and sequential rewiring of the micro-environment in the mammary gland.
SUCCESSion will have a ground breaking impact from a technical point of view as it will establish a novel way of modelling pre-cancer in vivo, and from a biological point of view as it will elucidate the temporal evolution of pre-cancer in unprecedented detail. This will lead to better understanding of tumour initiation and improve risk prediction enabling early interventions to stop the cancer before it starts.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics mutation
- medical and health sciences clinical medicine oncology
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2024-STG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
9052 ZWIJNAARDE - GENT
Belgium
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.