Description du projet
Le rôle des jonctions cellule-cellule dans la formation des métastases
La majorité des patientes atteintes d’un cancer du sein décèdent en raison de l’apparition de métastases distantes. Contrairement à l’idée actuelle selon laquelle les métastases sont disséminées par des cellules isolées de la tumeur initiale, une étude très récente portant sur des échantillons de sang de patients a révélé l’existence de groupes de cellules cancéreuses. Ces cellules sont maintenues ensemble par des jonctions cellulaires et forment des métastases jusqu’à 50 fois plus efficacement que les cellules cancéreuses isolées. Des données préliminaires révèlent que les desmosomes et les jonctions serrées sont impliqués dans le processus et représentent une cible pour le développement d’une thérapie spécifique aux métastases du cancer du sein. Le projet HOLDING-HANDS, financé par le CER, entend étudier les composants spécifiques des desmosomes et des jonctions serrées dans le développement des métastases, ainsi que leur rôle dans la signalisation cellulaire et la réponse au traitement.
Objectif
Breast cancer is the most common cancer in women, resulting in as many as 500000 deaths per year worldwide. Patients with breast cancer die unequivocally because of the development of incurable distant metastases and not because of symptoms related to the primary site. Understanding the complex, yet fundamental mechanisms driving breast cancer metastasis is critical to develop therapies tailored to this disease.
The current understanding of how metastasis occurs is derived primarily from mouse models and largely dominated by the notion that single migratory cancer cells within the primary tumor can actively disseminate to distant sites and develop as metastatic deposits. Unexpectedly, our very recent study on patient blood samples has shown that cancer cell groupings, held together through strong cell-cell junctions, can break off the primary tumor and form a metastatic lesion up to 50 times more efficiently than single migratory cancer cells (Aceto et al, Cell, 2014). These findings lead to new open questions, yet highlight a previously unappreciated and targetable mechanism of cancer dissemination.
Our preliminary data suggest that, among all types of cell-cell junctions, desmosomes and tight junctions are involved in this process, and therefore represent unprecedented options for developing a metastasis-tailored therapy for breast cancer.
The two predominant goals of this proposal are: first, to define the role of specific desmosome (DSG2) and tight junction (CLDN3 and TJP2) components in the development of metastasis. Second, to address their involvement in cellular signaling and response to therapy. These studies will not only use our first-of-a-kind in vivo models developed from patients with breast cancer metastases, but also cross the boundaries between basic science and clinical applications.
Our research has the long-term ambition to lead to a novel class of therapeutic agents tailored to block cell-cell junctions and prevent metastatic spread of cancer.
Champ scientifique
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Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
4051 Basel
Suisse