|Biblioteca NMS|FCM online
Ovarian Cancer (OC) is the 5th most common type of cancer in women worldwide and the leading cause of death from gynecologic cancer. The high mortality rate of OC is mostly due to the non-specific symptoms of this disease that culminate in a late-stage diagnosis, which may lead to the presence of metastasis. This cancer can typically disseminate to the peritoneal or pleural cavities. The shedding of the tumor cells from the primary tumors to these cavities leads to the accumulation of malignant ascitic fluid or malignant pleural effusion in these sites. These liquids are composed by tumor cells, fibroblasts, adipocytes, mesothelial, endothelial, and immune cells, varying between patients. Despite the high heterogeneity among patients, OC treatment is still based on the “one-size-fits-all” approach and the treatment consists of maximal surgery reduction combined with carboplatin+paclitaxel chemotherapy and maintenance with PARP inhibitors (Olaparib or Niraparib). Due to the heterogeneity of each cancer, treatment may prove to be successful for some patients but not for others. To personalize treatment, our lab is developing the zAvatars model to guide oncologists in the choice of the best treatment for each patient. zAvatars are patient derived zebrafish xenografts, where tumor cells from patients are directly injected into 2days post fertilization zebrafish embryos. zAvatars are then treated with the different therapy options and response to therapy is accessed after 3-4 days. The major goal of this work is to contribute to the development of the OC zebrafish Avatar model. Although Olaparaib was the first PARP inhibitor to be developed, Niraparib is now the main choice of oncologists. Our lab has previously developed a protocol to test Olaparib but not Niraparib. Thus, in this research project, I started by validating Niraparib efficacy, in order to use this PARP inhibitor as a possible OC treatment option for zAvatars. Our results showed that, indeed, we can evaluate the cytotoxicity of Niraparib in zAvatars. Next, we proceeded to generate OC zAvatars with the cells obtained from the ascitic fluid or malignant pleural effusions of 6 OC patients. In the generated zAvatars, not only we studied the response to therapy but also characterized the cells present in the tumors to validate the representativeness of the patient tumor in the zAvatar model. Our results showed that in general it was possible to identify the same type of cells in the smears and in zAvatars, namely, tumor cells and macrophages, identified by the PAX8, CA125, and CD68 staining. Also, in the smears it was possible to detect cancer associated fibroblasts (CAFs) using the α-SMA marker. After characterizing our model, we aimed at validating the zebrafish xenografts as a screening platform for OC therapies. In this dissertation, I will only present the results regarding one of the patients, since the results for the other patients were obtained by my supervisor, Dr. Marta Estrada. In the results presented for that patient, it was demonstrated that neither tumor implantation, metastasis capacity, cell death, nor tumor size were affected by the treatments. Overall, with the present work, we can conclude that tumors in zAvatars have a good representation of the different cell types present in the initial tumor sample. More specifically, we were able to observe the same cell markers in the smears and in the matching zAvatars.