Descripción del proyecto
Diferenciación forzada de células tumorales como nuevo tratamiento para el cáncer
Las interacciones entre los tumores y el microentorno suelen ser decisivas para descubrir los mecanismos de su supervivencia. El método alternativo para matar las células tumorales, ya sea directamente o a través del sistema inmunitario, consiste en forzarlas a diferenciarse. Esta estrategia resulta especialmente prometedora para los tumores derivados de poblaciones progenitoras que no siguieron las cascadas de diferenciación adecuadas. El proyecto financiado con fondos europeos KILL-OR-DIFFERENTIAT desarrollará un método sistemático para la caracterización de las interacciones intercelulares en microentornos complejos aplicando análisis de transcriptómica de células individuales disociadas a fin de identificar vías intercelulares que puedan inducir la diferenciación terminal en los tumores originados en la cresta neural.
Objetivo
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.
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Régimen de financiación
ERC-SyG - Synergy grantInstitución de acogida
1090 Wien
Austria