Summary
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.
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.
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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/101117339 |
| Start date: | 01-01-2024 |
| End date: | 31-12-2028 |
| Total budget - Public funding: | 1 911 428,00 Euro - 1 911 428,00 Euro |
Cordis data
Original description
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.
Status
SIGNEDCall topic
ERC-2023-STGUpdate Date
12-03-2024
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