Translational Research Symposium Speaker Spotlight: Professor Mark Shackleton

Professor Mark Shackleton

Monash University's 5th annual Translational Research Symposium is being hosted by its three metropolitan clinical schools on 21 June 2019. The symposium will host a diverse group of medical researchers presenting their work into translational research. RSVP here.

Professor Mark Shackleton is Director of Oncology at Alfred Health and Professor of Oncology in the Department of Medicine, Monash University.
Prof Mark Shackleton is the Director of Oncology at Alfred Health, a Professor of Oncology at Monash University, a Victorian Cancer Agency Clinical Research Fellow and Chair of Melanoma and Skin Cancer Trials Inc. After training in medical oncology and at the Ludwig Institute in Melbourne, he undertook PhD studies at the Walter and Eliza Hall Institute of Medical Research and post-doctoral work at the University of Michigan, USA. He has received several major prizes for his research: the 2006 Victorian Premier’s Award for Medical Research, a 2010 NHMRC Achievement Award, a 2011 Pfizer Australia Fellowship, and a 2016 Victorian Cancer Agency Clinical Research Fellowship. In 2012, he was awarded the Australian Science Minister’s Prize for Life Scientist of the Year.

Professor Shackleton's presentation abstract can be found below:
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Investigating melanoma heterogeneity

In histological assessments of melanomas, we found a high degree of intratumoral heterogeneity (ITH) for melanin pigment production, even in overtly pigmented tumors. Using a novel flow cytometry approach to prospectively separate cells according to pigment content, we found that low-pigment cells are abundant and have enhanced clonogenic potential in vitro and tumorigenic potential in vivo, compared to high-pigment cells. Moreover, low- but not high-pigment cells generated progeny that recapitulated the pigment heterogeneity of the original tumor or cell line.

Transcriptome profiling of low- and high-pigment cells suggested drivers of heritable functional distinctions between them. By gene ontology and Gene Set Enrichment Analysis, high-pigment cells showed increased expression not only of markers of melanocytic differentiation, but also of p53 activation. In contrast, low-pigment cells displayed gene expression patterns associated with ribosome biogenesis and Myc-activation. We therefore treated heterogeneously pigmented cell lines with the RNA Polymerase I inhibitor CX5461, which inhibits ribosome biogenesis. CX5461 increased pigmentation and senescence markers while markedly and irreversibly decreasing clonogenicity.

Our data are inconsistent with proposed plastic relationships in melanoma between high- and low-pigment melanoma cells. Rather, we find evidence in pigmented melanomas of relatively flat cellular hierarchies, with low-pigment cells at a broad apex of the hierarchy that both self-renew as well as generate high-pigment cells that are irreversibly non-clonogenic. We also find that this may be exploited therapeutically by inhibiting mechanisms such as ribosome biogenesis that apparently sustain the highly clonogenic, low-pigment state.
   
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We look forward to welcoming Professor Shackleton for the Symposium!

More information:
Translational Research Symposium

• Date: Friday 21 June 2019
• Time: 8:30 for 9:00am start - 5:30pm close
• RSVP here

Find out more about the symposium and our speaker program.

If you are a graduate student or early career researcher, you may be interested in the Young Investigator poster competition. See here for more details and to RSVP.