The project aims to investigate and therapeutically target mechanisms of resistance and MRD in AML, which rely on the bone marrow microenvironment, and particularly mesenchymal stromal cells (MSCs).
The researcher will build on single-cell genomic, transcriptomic and epigenomic data in MRD to perform 1) bioinformatic analysis of the interactome of AML resistant to chemotherapy or venetoclax-azatidine (VEN/AZA) with the bone marrow microenvironment and particularly MSCs; 2) supervised analysis and cross-comparison with candidate microenvironment-dependent vulnerabilities identified in MIRACLE’s AI-based and functional CRISPR-Cas9 screening to 3) model the key interactions using an innovative “organ-on-chip” 3D model adapted to include MSCs and other relevant cell types studied using cutting-edge supra-resolution time-lapse confocal imaging; 4) test candidate compounds and genetic gain- and loss-of-function models targeting the top new pathways identified and 5) validate the key targets identified ex vivo using PDX models in vivo.
In parallel to the discovery pipeline outlined above, starting in the first year the researcher will test candidate pathways already identified, to expedite the translational potential of the project and increase the overall success rate.
Host:
University of Sevilla, Sevilla, Spain
Supervisor:
Prof. Simon Mendez-Ferrer
Duration:
48 months, starting 1-5-2025
Profile doctoral candidate:
Master’s degree in life sciences, other (bio)medical sciences, or related, and practical experience in cell biology, molecular biology, and basic bioinformatics.