📋 Tender Overview
Unmasking The Dynamic Influence Of The Hematopoietic Niche As An Oncogenic Path To Myeloid Neoplasms Evolution
Funded Under
European Research Council (Erc)
Total Cost
€ 1 911 428,00
Eu Contribution
€ 1 911 428,00
Coordinated By
Universite Paris Cite
France
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.
