ULCaN Seminar Series
Time and Date
Friday, 29th January 2021, 1pm
(via MS Teams)
Microsoft Teams meeting
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Dr Catriona Dowling, University of Limerick
Identifying and targeting metabolic vulnerabilities in cancer
Metabolic reprogramming is a hallmark of cancer which contributes to essential processes required for cancer. Recent advances in biochemical and molecular biological tools has reignited the metabolic field and offered an unprecedented opportunity to unravel and delineate many aspects of cancer metabolism in more depth. We set up a phenotypic small molecule screen to reveal vulnerabilities in triple negative breast cancer (TNBC) cells. Using a functional genetic approach, we identified that a ‘hit’ compound, BAS-2, had potentially a similar mechanism of action to histone deacetylase inhibitors (HDAC), based on its RNAi signature. An in vitro HDAC inhibitor assay, confirmed that the compound selectively inhibited HDAC6 (>250 fold selectivity). By measuring the acetylome and interactome of HDAC6 using mass spectrometry, we identified new substrates of HDAC6 in TNBC cells. Remarkably, we found that HDAC6 bound to and altered four key glycolytic enzymes and we confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Moreover, we identified similar metabolic effects in a specific genotype of non-small cell lung cancer (NSCLC). We observe a dependency on the nicotinamide adenine dinucleotide (NAD+) salvage pathway in this specific genotype of NSCLC, which is further enhanced upon treatment with a HDAC6 inhibitor. Through a series of unbiased screening approaches we have identified a new role for HDAC6 in regulating metabolism.
Catríona received a BSc (education) and a research MSc in animal physiology at the University of Limerick. In 2012, Catríona secured a scholarship from the Irish Cancer Society to pursue a PhD in cancer biology at the University of Limerick. During this time, Catríona received an international mobility grant from the Irish Cancer Society to carry out a research in University of California San Diego. Following her PhD, Catríona undertook post-doctoral work at the Royal College of Surgeons in Ireland, during which time she secured independent fellowships from the Irish Research Council and Marie Skłodowska-Curie Action Global Fellowship. Subsequently, Catríona spent two years at the Perlmutter Cancer Centre at the NYU Langone Health in New York. In 2020, Catríona joined the School of Medicine as a Lecturer in Biomedical Sciences. Catríona’s current research interests are focused around manipulating the intrinsic metabolic rewiring in lung cancer cells to enhance anti-tumor immunity.