Spatial proteomics finds CD155 and Endophilin-A1 as mediators of growth and invasion in medulloblastoma

The composition of the plasma membrane (PM)-associated proteome of tumor cells determines cell-cell and cell-matrix interactions and the response to environmental cues. Whether the PM-associated proteome impacts the phenotype of Medulloblastoma (MB) tumor cells and how it adapts in response to growth factor cues is poorly understood. Using a spatial proteomics approach, we observed that hepatocyte growth factor (HGF)-induced activation of the receptor tyrosine kinase c-MET in MB cells changes the abundance of transmembrane and membrane-associated proteins. The depletion of MAP4K4, a pro-migratory effector kinase downstream of c-MET, leads to a specific decrease of the adhesion and immunomodulatory receptor CD155 and of components of the fast-endophilin-mediated endocytosis (FEME) machinery in the PM-associated proteome of HGF-activated MB cells. The decreased surface expression of CD155 or of the fast-endophilin-mediated endocytosis effector endophilin-A1 reduces growth and invasiveness of MB tumor cells in the tissue context. These data thus describe a novel function of MAP4K4 in the control of the PM-associated proteome of tumor cells and identified two downstream effector mechanisms controlling proliferation and invasiveness of MB cells

Discovery of a small molecule ligand of FRS2 that inhibits invasion and tumor growth

Purpose: Aberrant activation of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases drives oncogenic signaling through its proximal adaptor protein FRS2. Precise disruption of this disease-causing signal transmission in metastatic cancers could stall tumor growth and progression. The purpose of this study was to identify a small molecule ligand of FRS2 to interrupt oncogenic signal transmission from activated FGFRs. Methods: We used pharmacophore-based computational screening to identify potential small molecule ligands of the PTB domain of FRS2, which couples FRS2 to FGFRs. We confirmed PTB domain binding of molecules identified with biophysical binding assays and validated compound activity in cell-based functional assays in vitro and in an ovarian cancer model in vivo. We used thermal proteome profiling to identify potential off-targets of the lead compound. Results: We describe a small molecule ligand of the PTB domain of FRS2 that prevents FRS2 activation and interrupts FGFR signaling. This PTB-domain ligand displays on-target activity in cells and stalls FGFR-dependent matrix invasion in various cancer models. The small molecule ligand is detectable in the serum of mice at the effective concentration for prolonged time and reduces growth of the ovarian cancer model in vivo. Using thermal proteome profiling, we furthermore identified potential off-targets of the lead compound that will guide further compound refinement and drug development. Conclusions: Our results illustrate a phenotype-guided drug discovery strategy that identified a novel mechanism to repress FGFR-driven invasiveness and growth in human cancers. The here identified bioactive leads targeting FGF signaling and cell dissemination provide a novel structural basis for further development as a tumor agnostic strategy to repress FGFR- and FRS2-driven tumors. Keywords: Bioactive small molecule compound; Cell invasion; FGFR; FRS2; Protein–protein interaction interference; Thermal proteome profilin

Etude des Histones Désacétylases (HDACs) comme cibles thérapeutiques dans le cancer gastrique

Due to the efficiency of treatments, the 5-year overall survival rate for patients with gastric cancer (GC) is approximately 15%. Currently, there is no stratification of patients to prescribe an effective treatment protocol.During my thesis, I established the role of HDAC4 in the sensitivity of GC cells to Cisplatin. I have shown that this response seems to depend on the type of GC (intestinal or diffuse) and the p53 status of cancer cells. I emphasized the interest of combining an HDAC inhibitor (SAHA) with platinum derivative chemotherapies (PDC: Cisplatin, Oxaliplatin) to promote their cytotoxic effects. Interestingly, I observed that the response to combination treatments is different depending on the p53 status of the cancer cells.These results open new perspectives in the use of PDC + SAHA combination therapies in GC. The p53 factor that is often mutated in GC could be a therapeutic marker for a such treatment protocol.En raison de l’efficience des traitements, le taux de survie globale à 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma thèse, j’ai établi le rôle de HDAC4 dans la sensibilité des cellules de CG au Cisplatine. J’ai montré que cette réponse semble dépendre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancéreuses. J’ai souligné l’intérêt de combiner un inhibiteur des HDACs (SAHA) avec les chimiothérapies à base de dérivés de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De manière intéressante, j’ai observé que la réponse aux traitements combinés est différente suivant le statut p53 des cellules cancéreuses. Ces résultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combinés PDC + SAHA dans la thérapie du CG. En particulier, le facteur p53 qui est souvent muté dans les CG, pourrait être un marqueur thérapeutique pour un tel protocole de traitement

Study of Histone deacetylases (HDAC) as therapeutic targets in gastric cancer

En raison de l’efficience des traitements, le taux de survie globale à 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma thèse, j’ai établi le rôle de HDAC4 dans la sensibilité des cellules de CG au Cisplatine. J’ai montré que cette réponse semble dépendre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancéreuses. J’ai souligné l’intérêt de combiner un inhibiteur des HDACs (SAHA) avec les chimiothérapies à base de dérivés de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De manière intéressante, j’ai observé que la réponse aux traitements combinés est différente suivant le statut p53 des cellules cancéreuses. Ces résultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combinés PDC + SAHA dans la thérapie du CG. En particulier, le facteur p53 qui est souvent muté dans les CG, pourrait être un marqueur thérapeutique pour un tel protocole de traitement.Due to the efficiency of treatments, the 5-year overall survival rate for patients with gastric cancer (GC) is approximately 15%. Currently, there is no stratification of patients to prescribe an effective treatment protocol.During my thesis, I established the role of HDAC4 in the sensitivity of GC cells to Cisplatin. I have shown that this response seems to depend on the type of GC (intestinal or diffuse) and the p53 status of cancer cells. I emphasized the interest of combining an HDAC inhibitor (SAHA) with platinum derivative chemotherapies (PDC: Cisplatin, Oxaliplatin) to promote their cytotoxic effects. Interestingly, I observed that the response to combination treatments is different depending on the p53 status of the cancer cells.These results open new perspectives in the use of PDC + SAHA combination therapies in GC. The p53 factor that is often mutated in GC could be a therapeutic marker for a such treatment protocol

Study of Histone deacetylases (HDAC) as therapeutic targets in gastric cancer

En raison de l’efficience des traitements, le taux de survie globale à 5 ans des patients avec un cancer gastrique (CG) est d’environ 15%. A l’heure actuelle, il n’existe pas de stratifications des patients permettant de prescrire un protocole de traitements efficace. Durant ma thèse, j’ai établi le rôle de HDAC4 dans la sensibilité des cellules de CG au Cisplatine. J’ai montré que cette réponse semble dépendre du type de CG (intestinal ou diffus) et du statut p53 des cellules cancéreuses. J’ai souligné l’intérêt de combiner un inhibiteur des HDACs (SAHA) avec les chimiothérapies à base de dérivés de platine (PDC : Cisplatine, Oxaliplatine) afin de promouvoir leurs effets cytotoxiques. De manière intéressante, j’ai observé que la réponse aux traitements combinés est différente suivant le statut p53 des cellules cancéreuses. Ces résultats permettent d’ouvrir de nouvelles perspectives dans l’utilisation des traitements combinés PDC + SAHA dans la thérapie du CG. En particulier, le facteur p53 qui est souvent muté dans les CG, pourrait être un marqueur thérapeutique pour un tel protocole de traitement.Due to the efficiency of treatments, the 5-year overall survival rate for patients with gastric cancer (GC) is approximately 15%. Currently, there is no stratification of patients to prescribe an effective treatment protocol.During my thesis, I established the role of HDAC4 in the sensitivity of GC cells to Cisplatin. I have shown that this response seems to depend on the type of GC (intestinal or diffuse) and the p53 status of cancer cells. I emphasized the interest of combining an HDAC inhibitor (SAHA) with platinum derivative chemotherapies (PDC: Cisplatin, Oxaliplatin) to promote their cytotoxic effects. Interestingly, I observed that the response to combination treatments is different depending on the p53 status of the cancer cells.These results open new perspectives in the use of PDC + SAHA combination therapies in GC. The p53 factor that is often mutated in GC could be a therapeutic marker for a such treatment protocol