Vanderhyden Lab

Barbara Vanderhyden profile picture

Contact Information

Barbara Vanderhyden, PhD
613-737-7700 ext. 70330
bvanderhyden@ohri.ca

Ottawa Hospital Research Institute
Centre for Cancer Therapeutics
501 Smyth Road
Box 926
Ottawa, ON K1H 8L6

ORCID logo https://orcid.org/0000-0002-7644-7189

Research Activities

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. 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. 

High-throughput genomics to investigate models of ovarian cancer
Recent advances in genomics have enabled interrogation of gene activity and function at unprecedented resolution. The Vanderhyden lab employs newer technologies like single cell RNA-sequencing and CRISPR library screens to map gene expression patterns associated with 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 BRCA1mutation 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 hormone-induced GREB1. In addition to animal models, we assess translational relevance in primary cultures of human ovarian cancers, cancer cell lines, and ascites.

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. We are also determining how those risk factors affect the ovarian microenvironment and underlying mechanisms that contribute to the creation of a more tumour-permissive niche. 

Chromatin remodelling proteins and changes in cell state
Shifts in cell state require changes in gene expression that are dependent on chromatin remodelling in the nucleus. Shifts between proliferation and differentiation, or between epithelial and mesenchymal states involve chromatin remodelling complexes as key modulators of nucleosome positioning to regulate gene expression. We are investigating the expression and function of several chromatin remodellers encoded by Smarcagenes, including the balance between SMARCA5 (SNF2H) and SMARCA1 (SNF2L), proteins that seem to play a role in regulating cellular proliferation vs. differentiation in reproductive tissues. As normal differentiation of cells is essential for female fertility, this project aims to determine the role of these proteins in embryonic development, follicle growth, corpus luteum formation and placental function. 

Chromatin remodelling proteins in SCCOHT tumours
One of the mouse models of ovarian cancer we have developed is a model for small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). This model has enabled many collaborative studies aiming to identify possible treatments for patients with this rare disease. With the recent discovery that SCCOHT tumours often carry a mutation in SMARCA4, we are currently exploring two important questions that remain unanswered: What is the cell of origin of SCCOHT and how does loss of SMARCA4 cause its transformation? Both of these questions are being answered using mice with ovarian cell-specific deletion of Smarca4. We aim to generate an immune-competent model of SCCOHT, validated to have a molecular profile similar to human SCCOHT, that will enable future critical experiments for preclinical testing of novel therapeutic strategies for this aggressive disease.