Description du projet
La différenciation forcée des cellules tumorales comme nouveau traitement contre le cancer
Les interactions entre les tumeurs et le microenvironnement sont souvent critiques pour découvrir les mécanismes de leur survie. L’approche alternative consistant à tuer les cellules tumorales, directement ou par le biais du système immunitaire, consiste à les forcer à se différencier. Cette stratégie est particulièrement prometteuse pour les tumeurs issues de populations progénitrices qui ne sont pas parvenues à suivre leurs propres cascades de différenciation. Le projet KILL-OR-DIFFERENTIAT, financé par l’UE, développera une approche systématique pour la caractérisation des interactions intercellulaires au sein de microenvironnements complexes, appliquant une analyse de la transcriptomique de cellules uniques dissociées pour identifier les voies intercellulaires susceptibles de pousser les tumeurs originaires de la crête neurale vers la différenciation terminale.
Objectif
The interactions between tumor and its microenvironment are often critical to uncovering the mechanisms of tumor survival. A striking example is the recent success of immunotherapy approaches that expose tumor cells to immune attack by disrupting a specific interaction between the tumor and infiltrating lymphocytes. The tumor can also repress immune response by inducing complex interactions among dozens of immune and stromal cell types that typically make up tumor microenvironment, however those remain largely uncharacterized as we currently lack systematic approaches to uncover relevant cell-cell interactions. The alternative to killing tumor cells, either directly or through immune system, is to force them to differentiate. Such strategy is particularly promising for tumors arising due to failure of progenitor populations to follow proper differentiation cascade. Here as well, the progress has been limited by lack of understanding of specific intercellular signals that that are disrupted in tumorigenesis.
We propose a systematic approach for characterizing cell-cell interactions in complex microenvironments through joint analysis of spatially-resolved and disassociated single-cell transcriptomics. We will apply it to identify inter-cellular signals and pathways that can push tumors of neural crest origin, including as pheochromocytoma (PCC), paraganglioma (PGL) and neuroblastoma (NB), towards terminal differentiation. Building on our expertise with neural crest development, we will use single-cell profiling to map individual tumor cells onto developmental trajectory of neural crest differentiation. Spatial transcriptomics analysis will then be used to identify the sources and nature of microenvironment signals that channel neural crest differentiation during normal development. Contrasting interactions in normal and tumor tissues we will then aim to identify factors, pathways or signals that would push that PCC, PGL and NB tumors towards benign state.
Champ scientifique
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-SyG - Synergy grantInstitution d’accueil
1090 Wien
Autriche