Understanding the role of epigenetic regulators in cancer biology.
The most commonly mutated genes in cancer are known as ‘epigenetic regulators’. They are responsible for controlling gene expression, DNA repair and replication. Because the epigenome is highly dynamic, these genes are considered key targets for cancer treatments.
Led by Professor Mark Dawson, a clinician-scientist at the Peter MacCallum Cancer Centre and University of Melbourne, the Cancer Epigenetics Lab is at the forefront of international research on the role of epigenetic regulators in cancer biology. They aim to use these insights to identify novel therapies for the treatment of a range of haematological and solid cancers.
The multidisciplinary team has broad expertise spanning biochemistry, cell biology, molecular biology, genomics, chemical biology, immunology, animal models of disease and bioinformatics. They use clinically relevant models to identify epigenetic regulators which are important for cancer initiation, maintenance and progression.
Underpinning this research are unbiased genetic screens using RNA interference (RNAi) or gene editing (CRISPR/Cas9) and single cell analytical platforms.
Curiosity-based research is central to the culture of the Cancer Epigenetics Lab, which seeks to make important scientific discoveries that may ultimately be translated into early-phase clinical trials.
Research Projects
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An enduring ambition for the lab is to develop novel therapies that target epigenetic regulators in cancer. Their research in this area employs cutting-edge genetic screens to deliver a detailed molecular understanding of the role of various epigenetic regulators in the initiation and maintenance of cancer.
This work has already provided the framework for the development of several first-in-class therapies (Dawson et al; Nature 2011; MacPherson et al; Nature 2020; Gilan et al; Science 2020) and helped establish the platform for more than 30 clinical trials in over 20 countries.
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The Cancer Epigenetics Lab’s research has highlighted that chronic viral infections and ongoing inflammation favour the emergence of clonal haematopoiesis (Dharan et al; Nature Medicine 2019). Several projects in the lab have developed a suite of innovative reagents (Fennell et al; Nature 2022) that enable the temporal and spatial assessment of clonal behaviour at single cell resolution in clinically relevant models. It’s hoped these advances will aid in further studies assessing the contribution of clonality to normal development, ageing and cancer.
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The Cancer Epigenetics Lab’s research illustrates that therapeutic resistance can arise from cancer stem cells in the absence of genetic evolution, through a process of transcriptional plasticity (Fong et al; Nature 2015; Agarwal et al; Nature Medicine 2019 & Bell et al; Nature Communications 2019).
These findings have been instrumental in establishing the importance of non-genetic mechanisms of therapeutic resistance in cancer. Ongoing work in the lab aims to identify how the cancer genome instructs cancer cell plasticity.
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A large focus of ongoing research in the laboratory has been to investigate the mechanisms by which epigenetic proteins regulate anti-cancer immune surveillance (Burr et al; Nature 2017; Burr et al; Cancer Cell 2019; Chan et al; Cancer Cell 2022; Sparbier et al; Nature Cell Biology 2023, Guirguis et al; Cancer Discovery 2023).
Ongoing work involves enhancing CAR-T function and leveraging the proteins that chemically modify DNA and RNA to enhance anti-cancer immunity.
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The laboratory works collaboratively with medicinal chemists in academia and pharma to develop novel strategies to study a range of molecular processes in cancer (Tyler et al; Science 2017; Garciaz et al Cancer Discovery 2022).
Ongoing projects in the lab have also leveraged several approaches for acute targeted chemical degradation of cellular proteins to identify their contribution to a range of cellular processes including transcription, cell cycle progression and cell death.
Exploring the specialised functions of certain cells has enabled us to develop more targeted therapies. Asking questions and searching for answers is what drives scientific discoveries forward. Professor Mark Dawson
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Professor Mark Dawson
The Sir Peter MacCallum Department of Oncology
mark.dawson@petermac.org