UQCCR Seminar Series - 17 February 2021 - Dr Emanuele Pelosi and Dr Jodi Saunus

Dr Emanuele Pelosi - Genetics of the ovarian reserve: the master genes Foxl2 and Foxo3

Overview: The ovarian reserve consists of primordial follicles whose population is established before birth and decreases until menopause ensues around the age of 51. Premature depletion of the reserve results in primary ovarian insufficiency (POI), defined as menopause occurring before age 40, and affecting 1% of women. The genetics of POI is poorly defined, and the aetiology remains unexplained in 90% of cases. Two transcription factors, Foxl2 and Foxo3, sit at the crux of ovarian development, and can be targeted to modulate follicle dynamics, fertility, and reproductive lifespan. Using animal models, we are characterizing their roles in follicle survival and maintenance, and the part they play in menopause-associated conditions.

Bio: Dr Pelosi received his PhD in Medical Biotechnology in 2006. He worked at the National Institute of Health, USA, where he studied sex determination, ovarian development, and premature menopause. He joined the University of Queensland in 2016, establishing an international and multidisciplinary team of clinicians and researchers to define the aetiology of DSD.

Dr Jodi Saunus - Epigenome erosion drives developmental phenotypic mimicry in triple-negative breast and other SOX10+ cancers

Overview: Triple-negative breast cancers (TNBC) are molecularly heterogeneous, and the degree of variability in individual tumours is directly related to cancer relapse. We have been studying a type of heterogeneity called plasticity, which describes how some cancer cells can fluctuate between different phenotypic states. This capability is programmed epigenetically, so the changes are heritable and subject to natural selection just like genetic mutations. But epigenetic changes are unique in that they can be induced by environmental stress, and there is now evidence that adaptive chromatin remodelling can produce tolerance to chemotherapy. Remodelling is possible because in TNBC and other high-grade cancers, epigenetic marks that normally restrict chromatin accessibility in a tissue-specific manner are eroded, and the genome is a hypomethylated ‘blank canvas’.

We paired classical molecular pathology analysis with systems-level transcriptomics to study the biological and clinical significance of a cell state transcription factor called SOX10. We found that its TNBC-specific gene regulatory network confers poor prognosis and phenotypic similarity to neural crest stem cells of the embryo. Pan-cancer network analysis showed that developmental reprogramming also occurs in other SOX10+ cancers (melanoma and glioma) and correlates strongly with genome hypomethylation; particularly at sites of cell type-specific methylation called CpG island shores. We propose that without the restrictions imposed by this epigenetic fingerprint, cell state specifiers like SOX10 recreate their ancestral gene regulatory circuits by default. These findings have biological implications for understanding the roots of developmental phenotypic mimicry in cancer, and support preclinical data on the potential for chromatin remodelling inhibitors (e.g. JQ1) for limiting chemoresistance.