Veveeyan Suresh - Druggable pathways in EMT-like transition of Ewing sarcoma
PhD project 8: Ewing sarcoma
|Institute:||St. Anna Children's Cancer Research Institute|
|Supervisor:||Prof. Dr. Heinrich Kovar|
|Co-Supervisors:||Prof. Dr. Beat Schäfer and Dr. Silvia Boj|
|Doctoral Program:||Malignant Diseases|
|Secondments:||UZH (Switzerland) and HUB for Organoids (Netherlands)|
Identifying and targeting of key molecular determinants of migratory and invasive capacity in Ewing sarcoma. Fluctuations in the driver oncogene EWS-FLI1 have previously been reported to initiate epithelial-to-mesenchymal-transition (EMT)-like phenotypic changes in Ewing sarcoma through activation of YAP/TAZ/TEAD signalling. Accordingly, blocking YAP/TAZ/TEAD complex formation by a small molecule inhibitor (verteporfin) reduced tumour cell migration and the metastatic potential of Ewing sarcoma in a mouse model. We will mimic EWS-FLI1 fluctuation in two genetically modified Ewing sarcoma cell lines with small molecule-inducible EWS-FLI1 degradation and quantify migratory and invasive capacity of tumour cells using Boyden chamber assays. We will perform a pooled CRISPR/Cas9 drop-out screen to identify molecular dependencies of Ewing sarcoma EMT-like transitions using migratory and invasive capacity as read-out. In addition, we will screen a compound library of 309 unique drugs (CLOUD) including verteporfin for single and pairwise combinatorial activity on tumour cell migration. Novel targets and compound combinations will be validated in PDX-derived Ewing sarcoma cells using a novel 3D bio printed scaffold model recently established in the lab, and in a Ewing sarcoma xenograft model in zebrafish larvae.
We expect to identify molecular key players of the early steps of Ewing sarcoma metastasis, and to propose novel therapeutic drug combinations.