Unravelling ChemoResistance mechanisms and improving first-line therapeutic strategies in high-grade serous Ovarian Carcinoma using multi-culture patient-derived organoids

To improve the poor clinical outcomes in high-grade serous ovarian carcinoma (HGSC), we need to understand the cancer cell-tumour microenvironment (TME) dynamic interactions upon disease evolution and treatment.

In my proposed project, I will establish a unique TME-HGSC patient-derived organoid (PDO) multi-culture model system to identify and understand how the TME impacts treatment responses and how treatment resistance can be overcome.To generate multi-culture PDO preclinical models of HGSC for the first time, I will use my own expertise in 3D culture and stromal cell isolation from patient-derived material, and I will integrate self-generated TME units with well-characterized HGSC PDOs established at the host laboratory.

I will then use this model to study the chemotherapy-induced changes at the single cell level.

I will compare the transcriptional states of the treated models to the interval/recurrent PDOs and correlate their in vitro treatment responses to the patient responses.

I will predict strategies to increase the sensitivity of the cancer cells to the HGSC standard treatment by targeting the tumour-TME interactions or the cancer cells themselves without generating a more tumour-supportive TME, by using the multi-culture PDOs in high-throughput drug screens and subsequently integrating the generated data.

Finally, I will functionally validate the predicted therapeutic strategies by CRISPR gene editing and drug treatment of the models.I expect that my project will generate profound knowledge on the chemoresistance mechanisms in HGSC and provide the scientific community with a unique experimental model that incorporates the TME to state-of-the-art HGSC PDOs.

In addition, this fellowship will allow me to enhance my international visibility through high-impact publications independent from my PhD supervisor and provide me with a great track record in obtaining independent funding, essential to successfully secure independent research grants in the future.