Elucidating the Spatial and Temporal Dynamics of Acute Myeloid Leukemia Progression Using Functional Omics and High-Throughput In Vivo Screening (DynAML)

Framework: Horizon Europe — Excellent Science
Programme: European Research Council (ERC)
Theme: European research council
Destination: Consolidator grants
Action type: ERC actions
Panel: Physiology in Health, Disease and Ageing
Panel description: Organ and tissue physiology, comparative physiology, physiology  of ageing , pathophysiology, inter - organ and tissue communication, endocrinology, nutrition,  metabolism, interaction with the microbiome, non -communicable diseases including cancer (and except disorders of the nervous system  and immunity -related diseases)
Countries involved: France
Call: ERC CONSOLIDATOR GRANTS (ERC-2022-COG, 2022)
Start date: 2024-03-01
End date: 2029-02-28
Duration (months): 60.0
Total project cost (EUR): 1994500.0
EU funding (EUR): 1994500.0
Participants: 1
Project status: SIGNED

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.

Keywords: preclinical mouse models of acute myeloid leukemia,multi omics analyses and in vivo loss of function screening approaches,relationship between host tissue and leukemia progression,influence of aging on leukemia malignity