Projektbeschreibung
Einblicke in die Rolle der Stammzellnische von Krebszellen
Gewebespezifische Stammzellen sind undifferenzierte Zellen, die sich selbst erneuern und verschiedene Zelltypen innerhalb des Gewebes erzeugen können. Der Erhalt und die Funktion von Stammzellen hängen von der Stammzellnische ab, einer spezialisierten Stelle in Gewebe. Das EU-finanzierte Projekt IntratumoralNiche arbeitet unter der Annahme, dass Tumore ähnliche Nischen haben, die Krebsstammzellen, das Tumorwachstum und die Metastasierung fördern. Die Forschenden wollen die Signalgebung der tumorinneren Nische herausfiltern, indem sie patientenderivierte Organoidkulturen und Tiermodelle mit Darmkrebs untersuchen. Die Ergebnisse werden die Rolle der verschiedenen Bestandteile der Nische bei der Tumorprogression offenlegen und so möglicherweise neue Behandlungsziele aufdecken.
Ziel
Purpose: Cells in a tumor are highly heterogeneous. The role and consequence of having multiple cell types within a cancer is mostly centered towards the function of cancer stem cells (CSCs) since they are the driving forces of tumor growth. However, the exact signaling cues that support CSC function remain to be understood. For instance, what are the roles of immediate descendant tumor cells in relation to CSC support? Do colorectal tumors make their own niche?
Preliminary data: To study communication between different cell types (heterocellular signaling) in human colorectal cancers (CRCs), my lab developed movieSTAR technology to mark CSCs in patient-derived CRC organoids (PDOs) for high-resolution live imaging of their dynamics and behavior. Although niche factor dependency decreases along the adenoma-carcinoma transition, we identified a strong interdependency between CSCs and other tumor cells in colorectal PDOs of malignant nature.
Hypothesis: We hypothesize a continuous existence of an intratumoral stem cell niche that remains essential for tumor growth and metastasis formation. Which types of heterocellular signaling support CSC function, especially at malignant stages, is unknown.
Approach: This project aims to define heterocellular signaling between CSCs and intratumoral niche cells. Therefore, I) we will combine our expertise in human organoid technology for in-depth characterization of the nature of heterocellular communication within the intratumoral niche, II) high-resolution live imaging of PDOs to interrogate heterogeneity of signaling activities at cellular resolution and in real-time, as well as III) in vivo mouse models for validation and further studies of essential intratumoral signaling pathways.
Innovation: Our integrative use of novel approaches will provide comprehensive insight into intratumoral niche function during tumorigenesis, establishing novel technologies for future cancer research and new concepts to improve cancer therapy.
Wissenschaftliches Gebiet
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
3584 CX Utrecht
Niederlande