Project description
The dynamics of cancer in space and time
Cancer has traditionally been regarded as an accumulation of mutations, but these alone do not explain tumour progression. Equally important factors are the ‘where’ (which tissue) and the ‘when’ (during lifespan) mutations appear. This is what the ERC-funded DynAML project set out to portray in mice. It will investigate how ageing and tissue affect malignity and the progression of acute myeloid leukaemia (AML) cancers. Through a series of functional omics experiments, researchers will pinpoint specific genes, and characterise their involvement in cancer progression in vivo. By describing the spatio-temporal dynamics of tumour development, DynAML has the promising potential to enhance our overall understanding of cancer.
Objective
Advances in sequencing-based phylogenetic studies applied to cancer evolution have led to the observation that the linear accumulation of oncogenic alterations over individuals lifespan does not match the late life pattern of cancer incidence. It has thus become clear that beyond the sequential accumulation of oncogenic driver mutations, additional factors also support cancer outgrowth. The temporal and spatial dynamics of tumor evolution represent two of the most critical mutation-independent variables to consider. Hence, we hypothesized that the dual features of aging and spatial dissemination promote critical fitness gains that are at least as significant as driver mutations in cancer. The goal of this proposal is to investigate the spatial and temporal determinants of tumor progression and to dissect the contributions of these processes to cancer pathogenicity.
Due to its quite unique occurrence pattern and propagation characteristics, Acute Myeloid Leukemia (AML) is the prototypical disease model that we have elected to template such spatiotemporal-dependent features of disease development. To study these features, we engineered two mouse models of leukemia dissemination and aging using serially-transplantable MLL-AF9-driven leukemic blasts. Using these two models, we propose to i) combine metabolomic- and epigenomic-based profiling to portray the spatiotemporal dynamics of leukemia growth; ii) deploy single-cell transcriptomics coupled with lineage tracing experiments to reveal the pre-deterministic attributes of such dynamics; and iii) leverage innovative multimodal in vivo shRNA and CRISPRa screening approaches to pinpoint and functionally characterize the critical age- and dissemination-related effector genes involved in leukemic progression. The comprehensive analysis of their unknown function will potentially define new therapeutic routes in AML, and, given the holistic nature of the spatiotemporal characteristics studied, in other cancers as well.
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.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- natural sciencesbiological sciencesgeneticsmutation
- medical and health sciencesclinical medicineoncologyleukemia
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
75654 Paris
France