Abstract
Ovarian cancer remains a deadly disease with the five-year survival rate for ovarian cancer patients at about 50%. Ovarian spheroids, clusters of 3D growing cells, are thought to promote ovarian cancer metastasis and serve as a reserve of cancer cells that are not responsive to chemotherapy. Understanding genes associated with spheroid growth and metastasis may identify pathways to target for ovarian cancer therapy. We have found that the transcriptional modulator BCL6 is active in ovarian spheroids. BCL6 is a highly-conserved oncogene originally found to drive malignant transformation in B-cell lymphoma. Although BCL6 is thought to be a transcriptional repressor, we and others have found that it also upregulates genes. Little is known about the role of BCL6 in ovarian cancer. Using the Cancer Genome Atlas (TCGA) data and CBioPortal, we found that BCL6 is amplified in about 20% of high-grade serous ovarian cancer patients. In addition, analysis of nuclear extracts from a number of ovarian cancer cell lines demonstrated that BCL6 is overexpressed in many ovarian cancer cell lines. To assess transcriptional activity, we used a BCL6-responsive reporter and we found that BCL6 was active in most of these cell lines. Having demonstrated that BCL6 is active in ovarian cancer cells, we wanted to determine if BCL6 affected the viability of these cells. Therefore, we transfected ovarian cancer cells with siRNA to BCL6, measured their viability, and found that BCL6 is important for ovarian cancer cell survival. Recognizing that spheroids occur in advanced ovarian cancer, we analyzed the effects of BCL6 in 3D formation using micropatterned plates and discovered that BCL6 is also important for 3D spheroid formation. A major problem in advanced ovarian cancer is metastasis; therefore, we wanted to determine if BCL6 plays a role in promoting metastasis. We overexpressed BCL6 or downregulated BCL6 with siRNA and performed a mesothelial clearance assay to assess the early steps in ovarian cancer metastasis. While overexpressing BCL6 enhanced mesothelial clearance by the ovarian spheroids, reducing BCL6 expression also reduced mesothelial clearance. This suggested that BCL6 promotes ovarian cancer metastasis. We are currently in the process of identifying BCL6 target genes that are involved in metastasis. Taken together, our data suggests that BCL6 is an important transcriptional modulator in ovarian cancer and that targeting BCL6 in the future may be a useful strategy to treat metastatic ovarian cancer.
Citation Format: Duc Ngoc Hong Nguyen, David F. Walker, David A. Frank, Sarah R. Walker. BCL6 promotes ovarian cancer metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2730.
