Deciphering tumorsphere biology in ovarian cancer
[eng] Epithelial ovarian cancer (EOC) is the fifth-leading cause of cancer death among women and the most lethal gynecological malignancy. High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and aggressive subtype, accounting for 70% of ovarian cancer deaths. Survival rates are low due...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/219148 |
| Acceso en línea: | https://hdl.handle.net/2445/219148 http://hdl.handle.net/10803/693850 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer d'ovari Metàstasi Tumors Ovarian cancer Metastasis |
| Sumario: | [eng] Epithelial ovarian cancer (EOC) is the fifth-leading cause of cancer death among women and the most lethal gynecological malignancy. High-grade serous ovarian carcinoma (HGSOC) is the most prevalent and aggressive subtype, accounting for 70% of ovarian cancer deaths. Survival rates are low due to late-stage diagnosis and ineffective therapies for advanced disease. A significant number of patients develop ascites, which is associated with poor prognosis. This is due to the fact that transcoelomic dissemination is the main metastatic route of HGSOC, and involves cancer cells shedding from the primary tumor and clustering into tumorspheres, which are the main metastatic units in HGSOC and accumulate in the ascites. However, the molecular mechanisms behind their formation, proliferation and survival within the ascites microenvironment have long been unexplored. In this Doctoral Thesis, we demonstrate that PDGFRβ is essential for fibronectin-mediated cell clustering of ovarian cancer cells into tumorspheres. This effect is mediated by the kinase NUAK1 and blocked by PDGFRβ pharmacological or genetic inhibition. In the absence of PDGFRβ, ovarian cancer cells can be provided with fibronectin by cancer-associated fibroblasts (CAFs) to generate chimeric spheroids. On the other hand, we report that the S1P-S1PR1 ligand- receptor axis is especially relevant in ovarian tumorspheres, where it promotes an autocrine positive loop, serving as their primary proliferative mechanism via MEK1/2- ERK activation. Our findings demonstrate that the S1P-S1PR1-MEK1/2 pathway confers ovarian tumorspheres a selective advantage within the ascites environment and, consequently, increases their metastatic potential. Conclusively, our results shed light on the molecular mechanisms that direct tumorsphere formation and proliferation, which are critical for HGSOC metastatic spread and are orchestrated by PDGFRβ and S1PR1. The preclinical findings presented in this Doctoral Thesis may represent an opportunity to turn the main ovarian cancer’s metastatic potential promoters, tumorspheres, into this cancer’s Achilles’ heel. |
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