Project description
The role of the niche in the evolution of leukaemia
The haematopoietic niche or microenvironment plays a crucial role in the behaviour and function of blood cells, including their development, maintenance, and interaction with surrounding cells. Understanding the dynamics of the niche can provide important insight into its role in acute myeloid leukaemia development. Funded by the European Research Council, the OncoNichPath project will investigate the haematopoietic cell-niche communication during the pre-leukaemic, leukaemic and post-leukaemic stages. Using genomic screening and single-cell sequencing approaches, the long-term goal is to develop innovative therapeutic strategies to prevent the development and recurrence of myeloid leukaemia by reprogramming the niche from a ‘malignant’ to a ‘healthy’ state.
Objective
Although oncogenic driver mutations are found in healthy tissues sometimes at a prenatal stage, they do not often result in overt cancer. This genotype – phenotype discrepancy warrens the search for extrinsic mechanisms of cancer development and maintenance, such as aging or exposition to specific environments. Using myeloid neoplasms as a cancer model, I aim here at dissecting the hematopoietic-niche partnership at the “pre-leukemic”, “leukemic” and “post-leukemic” stage to identify innovative therapeutic strategies to prevent acute myeloid leukemia (AML) development, maintenance and recurrence.
To enable experimental modelling of the bone marrow niche at different disease stages, I collected longitudinal paired stromal and hematopoietic primary patient samples, and generated physiologically-relevant in vitro and in vivo humanized models. In this proposal, I will first apply large-scale pooled genetic screening approaches to gain insights into the role of the hematopoietic-niche cellular communication processes in leukemic transformation of “pre-leukemic” clonal myeloid conditions. In the second part of the proposal, I will combine cutting-edge spatial single-cell RNA sequencing technologies with functional genetic screening to dissect the “leukemic-niche” crosstalk and ultimately fuel the development of concomitant “seeds” and “soil” therapeutic strategies. Finally, I will design a functional single-cell screening approach allowing modulation of the “post-leukemic” niche, to open the road for novel maintenance treatment strategies re-establishing healthy hematopoietic stem cells fitness advantage to prevent relapse.
Overall, the proposed research project provides a framework for defining and understanding the dynamic influence of the hematopoietic niche as an oncogenic path to myeloid neoplasms evolution, and represents a key step towards therapeutic niche reprogramming from a “malignant” to a “healthy” state, to improve cancer patients’ prognosis.
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 medicineoncology
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
75006 Paris
France