How risk factors contribute to ovarian cancer initiation and progression
The Vanderhyden laboratory has a long-standing interest in normal ovarian function and the molecular changes that occur in the transition from normal epithelium to ovarian cancer, and the subsequent progression and metastasis of ovarian cancer. A key aim of our work is to examine the cellular plasticity and genetic alterations that are oncogenic in oviductal and ovarian surface epithelium. We are exploring how certain risk factors, like age, BRCA1 mutation, ovulation and hormones, affect the stem/progenitor cells in those tissues and their susceptibility to transformation into cancer cells. Our recent evidence that human and mouse ovaries develop fibrosis with age and that this can be blocked by treatment with metformin has greatly focused our attention on how those risk factors affect the ovarian microenvironment and underlying mechanisms that contribute to the creation of a more tumour-permissive niche.

Single cell RNA-Seq and bioinformatics to investigate models of ovarian cancer
The Vanderhyden lab employs newer technologies like single-cell RNA-sequencing to explore the transcriptomes involved in cancer susceptibility, initiation and progression. Application of these technologies to good model systems is critical to achieve clinically relevant outcomes. Animal models that spontaneously develop cancer enable us to understand the process of tumour formation and aid the investigation of novel prevention and treatment strategies, but there are few such models of ovarian cancer available. We have generated new transgenic and syngeneic mouse models of ovarian cancer to investigate the early events associated with tumour initiation, the impact of BRCA1 mutation and hormones on disease progression, and the testing of novel therapeutics. By identifying genetic alterations that are oncogenic in oviductal and ovarian surface epithelium, we are able to generate models of ovarian cancer using a variety of strategies, including cell-specific expression of oncogenic signals, the Cre-lox system for conditional expression, and intra-bursal injection of adenoviral vectors. Current genes under investigation include Lats1/Lats2 of the Hippo pathway, and the immunosuppressive Fgl2. In addition to animal models, we assess translational relevance in primary cultures of human ovarian cancers, cancer cell lines, and ascites.

Novel immune therapies for ovarian cancer
A combination of surgery and chemotherapy has been the standard of care for women with ovarian cancer for more than 40 years. While initially effective, most women develop recurrent disease which does not respond well to currently available treatments, although the introduction of PARP inhibitors can prolong survival in a subset of patients. In the past few years, cancer immunotherapy has emerged as a promising new approach to deal with difficult tumours in other tissues. This new class of treatment enables the immune system of the patient to fight the cancer, using their own natural defenses against pathogens. These immune therapies aim to overcome two major barriers to effective treatment: the loss of tumour immunogenicity and the highly immunosuppressive tumour microenvironment. We are developing combinatorial approaches to boost or restore the immune system’s ability to eliminate ovarian cancer cells using a number of different strategies for cancer immunotherapy, including targeted antibodies, cytokines, vaccines and oncolytic viruses.