The role of Wnt signaling in high-grade serous ovarian cancer stemness and therapy resistance
Ovarian cancer represents the deadliest gynecologic malignancy worldwide mainly due to the presentation of symptoms at late disease stages, i.e. when metastases are already spread to pelvic organs, the abdomen, or beyond the peritoneal cavity. Serous ovarian carcinomas represent the majority (70%) of the total cases, 90% of which are being accounted by the most aggressive subtype, namely high-grade serous (HGS) ovarian cancer. In fitting with its characteristic progression and recurrence patterns where a small subpopulation of malignant cells survive first-line debulking and underlie metastasis in abdominal organs, ovarian cancer is thought to encompass cancer stem cells (CSC). Notably, the Wnt/β-catenin signaling pathway, known to regulate stemness in a broad spectrum of stem cell niches including the ovary, is thought to play an important role in ovarian cancer: not only do β-catenin mutations characterize the endometrioid histotype, but alterations of its intracellular localization indicative of active Wnt signaling are often found in a substantial fraction of HGS ovarian cancers. Moreover, Wnt has been associated with resistance to therapy in ovarian cancer where it up-regulates ABC transporter pumps thus underlying chemo-resistance of CSCs to cisplatin and paclitaxel. Notably, our preliminary data indicate that the majority of HGS cell lines are Wnt-responsive, i.e. capable of activating Wnt in response to specific cues. This is of interest as we also showed that patient-derived ascites fluids can indeed stimulate Wnt in ovarian cancer cell lines.
The main goals of this project are:
- Study the cellular and molecular mechanisms underlying Wnt activation in HGS ovarian cancer;
- Elucidate its role in chemo-resistance to taxane- and platinum-based therapies;
- Explore the therapeutic efficacy of Wnt inhibition in HGS ovarian cancer.
We will study the modalities and consequences of Wnt activation in response to external stimuli in HGS ovarian cancer. The focus of our investigations will be on the upstream stimuli present in ascetic fluids and on downstream effects of Wnt signaling activation with focus on cancer stemness and resistance to chemotherapy. To this aim we will employ HGC ovarian cancer cell lines together with patient-derived xenografts (PDXs) and malignant ascites both in vitro (functional studies) and in vivo (preclinical studies). Moreover, mouse HGS cell lines will be employed to model HGS ovarian cancer in syngeneic hosts and study the molecular basis of chemoresistance to cisplatin and paclitaxel. This experimental approach will lay the basis for pre-clinical investigations in humanized mouse models to assess the therapeutic efficacy of a well-defined series of small molecule Wnt inhibitors currently being employed in clinical studies either as single agents or in combination with conventional cytotoxic drugs.
The proposed plan of investigation will contribute to the elucidation of the role played by Wnt activation in ovarian cancer stemness and chemo-resistance to cisplatin and paclitaxel. This will provide a rationale for the assessment of the therapeutic efficacy of small molecules which specifically target Wnt signaling in the treatment of ovarian cancer. Hence, the project has both translational and fundamental value, as it will contribute to our understanding of the molecular and cellular mechanisms underlying tumour onset, progression and therapy resistance of HGS ovarian cancer.