Descrizione del progetto
Metabolismo del piruvato e rimodellamento della matrice extracellulare per contrastare il cancro metastatico
Le metastasi, o tumori secondari, rappresentano la causa principale di morte dovuta al cancro. Molte pazienti affette da cancro al seno ricevono la diagnosi quando le cellule cancerogene si sono già propagate in organi distanti. Il rimodellamento della matrice extracellulare (MEC) nella nicchia metastatica è fondamentale affinché le cellule del cancro al seno propagate favoriscano la crescita delle nuove metastasi. Il laboratorio ospitante ha recentemente scoperto che il nutriente piruvato spinge metabolicamente le cellule del cancro al seno a rimodellare la MEC. Il progetto MetaTarGet, finanziato dall’UE, sta sfruttando questa scoperta per capire come contrastare il rimodellamento della MEC nelle metastasi. Lo studio si concentrerà sul metabolismo del piruvato quale regolatore del rimodellamento della MEC e come nuova strategia terapeutica per contrastare lo sviluppo metastatico.
Obiettivo
Distant metastases, i.e. secondary tumors, are the leading cause of cancer deaths. Many patients (especially with breast cancer) are diagnosed when cancer cells have already disseminated to distant organs. Thus, it is of profound importance to prevent the metastatic outgrowth of these disseminated cancer cells into secondary tumors. The ability to remodel the extracellular matrix (ECM) of the metastatic niche is essential for disseminated breast cancer cells to promote their own metastatic outgrowth. This process is to date believed to be transcriptionally regulated. However, the Fendt laboratory has discovered that the nutrient pyruvate metabolically drives ECM remodeling by breast cancer cells. In my project, I will build on this discovery and explore how to target ECM remodeling in metastatic outgrowth. First, I will determine the interaction between the discovered metabolic and the known transcriptional regulation of ECM remodeling. Secondly, I will translate this novel finding into therapeutic potential by defining how to selectively target it, thereby impairing metastatic outgrowth in the lung environment. Thirdly, I will define how the metastatic site and the cancer cell origin affect the discovered metabolic regulation of ECM remodeling, and thus metastatic outgrowth. To address these aims, I will use metabolomics, 13C tracer analysis, genetic engineering and nanotechnology-based drug-delivery in breast cancer 3D cultures and mouse models. With MetaTarGet, I will deliver (i) a mechanistic understanding of pyruvate metabolism as a regulator of ECM remodeling, and (ii) a novel therapeutic strategy to target metastatic outgrowth. This project will allow me to bridge my nanotechnology-based drug-delivery knowledge with the expertise of the Fendt laboratory in metastasis metabolism. Consequently, I will strengthen my research competences and enhance my personal research profile.
Campo scientifico
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Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
9052 ZWIJNAARDE - GENT
Belgio