Projektbeschreibung
Forcierte Differenzierung von Tumorzellen als neue Form der Krebsbehandlung
Die Wechselwirkungen zwischen Tumoren und ihrer Mikroumgebung sind oft von entscheidender Bedeutung, um die Mechanismen ihres Überlebens zu entschlüsseln. Die Alternative zur Abtötung der Tumorzellen (entweder direkt oder über das Immunsystem) besteht darin, sie zur Differenzierung zu zwingen. Besonders vielversprechend ist diese Strategie bei Tumoren mit Ursprung in Vorläuferpopulationen, die normalen Differenzierungskaskaden nicht folgen konnten. Das EU-finanzierte Projekt KILL-OR-DIFFERENTIAT wird einen systematischen Ansatz zur Charakterisierung der Zell-Zell-Interaktionen in komplexen Mikroumgebungen entwickeln. Anhand dieser neuen Methode werden die Forschenden Einzelzelltranskriptomik-Analysen erstellen und anwenden, um die interzellulären Signalwege zu identifizieren, die Tumore, die ihren Ursprung in der Neuralleiste haben, zur terminalen Differenzierung führen können.
Ziel
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.
Wissenschaftliches Gebiet
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Finanzierungsplan
ERC-SyG - Synergy grantGastgebende Einrichtung
1090 Wien
Österreich