Clonal events leading up to cancer initiation

Summary

We are seeking passionate Ph.D. and Masters candidates to conduct a research project on the cellular evolution of pre-cancerous tissue to tumour formation. We particularly encourage those from underrepresented groups (including women, First Nations People, people from a non-English speaking background, and people with disabilities) to apply.

Supervisor(s)

Dr Thomas Tu, Professor Jacob George

Research Location

Westmead - Westmead Institute for Medical Research

Program Type

Masters/PHD

Synopsis

Rather than just a simple accumulation of mutations, cancer formation can be thought of as a Darwinian process, where evolutionary pressures select for cellular clones that expand and eventually turn cancerous. Many cancers are the consequence of infectious diseases (e.g., cervical cancer, nasopharyngeal cancer, liver cancer) or environmental toxins (e.g., asbestos or UV light). In this project, we will study clonal events during cancer initiation using hepatitis B virus integration into host DNA as a model. This is thought to induce cellular changes resulting in cancer formation and reduced immune surveillance. This project will tease out the particular roles of DNA integration events in cancer formation.

Our previous studies showed that clonal cell proliferation prior to tumour formation is independent of the site of virus integration. Here, we focus on the identity of, transcription from, and mechanisms that result in virus integration into host DNA. We will use the following independent, but complementary approaches:
1. An in vitro model of integration combined with CRISPR-Cas9 gene editing. Here, we place integrations at specific cellular sites after infection with patient blood, allowing us to characterise the complete integrated sequences.
2. An in vivo model of integration. Here, we will observe how virus integration alters the growth of cells in its native liver microenvironment.
3. A high-throughput screening assay with a "reporter" virus. Here, we will undertake genome-wide screening (e.g. siRNA, CRISPR knock-out, cDNA library, etc.) of cellular targets to determine if the expression of certain genes increase the rate of integration.

Additional Information

Students working on this project can expect to learn the following techniques: CRISPR-Cas9-mediated gene editing, single-cell PCR, state-of-the-art microscopy, mathematical modelling, bioinformatics analysis, cell culture, virus production, animal handling, flow cytometry, and/or high-throughput screening assays.

About the Storr Liver Centre
The Westmead Clinical School's Storr Liver Centre focuses on the diverse range causes of liver diseases, including drugs and toxins, metabolic factors, and viruses. Internationally-acclaimed, the Centre has made outstanding contributions in defining the host responses to liver injury, understanding the underlying mechanisms of liver disease, and subsequent development of clinically-relevant bio-markers.
The Centre is well funded and employs cutting-edge techniques to bring each project to fruition. There will also be opportunities to collaborate with renowned researchers located both internationally and locally within the Westmead Institute for Medical Research. As part of the community of >400 researchers based on the Westmead hub, we are well equipped with state-of-the-art molecular, translational and cell biology facilities.

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Keywords

Liver, Cancer, hepatitis B, Evolution, infection, genomics

Opportunity ID

The opportunity ID for this research opportunity is: 2840

Other opportunities with Dr Thomas Tu

Other opportunities with Professor Jacob George