The Quinn Group's current research involves generating genetic models using the vinegar fly (Drosophila Melanogaster) to understand the initiation and progression of human cancer. Her core research uses in vivo cancer models to determine how complex developmental signalling pathways are integrated into transcriptional networks. In particular we aim to understand how these networks coordinate cell growth and division to establish the body plan during development, and also maintain tissue homeostasis in adult animals; as cell growth and proliferation are invariably dysregulated in human cancer. Her group also has a strong interest in using in vivo stem cell models to determine the mechanism(s) by which the stem cell microenvironment or “niche” regulates stem and progenitor cell growth, division and differentiation.
Available student projects:
Enquiries are welcome from potential Honours or PhD students. A variety of projects are available within all of areas of research undertaken by this Group. Contact Leonie by email or phone +61 2 612 56166.
Project 1 - Transcriptional control of the MYC oncogene
One core regulator of growth and division of great interest to our research is the MYC oncogene, which is a potent activator of cell growth networks and upregulated in most human cancers. As therapeutically targeting MYC itself has proved unfeasible, we need to find new ways to indirectly target MYC in cancer. Most MYC-driven cancer is due to upregulation of expression, but the networks controlling MYC transcription in malignancy are largely unknown. The single stranded DNA binding proteins FBP and FIR are essential for transcriptional control of the MYC oncogene, and dysregulation of this network is linked with a wide variety of cancers, eg. kidney, breast, liver, lung, bladder, prostate, gastrointestinal and brain. This research aims to use a combination of in vivo genetic models (Drosophila and mouse) and human cancer models to unravel the mechanisms for regulation of MYC expression by FBP/FIR.
Project 2 – Brain tumour models
With no effective drug treatments for malignant glioma these tumours are invariably lethal. One key discovery in glioma biology is that the EGFR/RAS/PI3K axis is activated in most gliomas. Indeed, preclinical trials are underway for therapeutics targeting PI3K/AKT and RAS/RAF in malignant glioma. Unfortunately, these studies have already revealed rapid acquisition of tumour resistance, which highlights the importance of understanding the activity of downstream targets. Elevated FBP and MYC correlate with poor patient survival, which suggests FBP and MYC abundance/activity might also be drivers of glioma malignancy. This project builds on our exciting observation that FBP is a critical downstream target of EGFR/RAS/PI3K. We aim to use Drosophila, mouse and human glioma models to determine how the FBP-MYC axis drives MYC expression and brain tumour growth. Given the capacity of FBP knockdown to extinguish RAS-activated MYC expression, we propose that FBP is an attractive future target for developing novel cancer therapies.
Project 3 – Leukemia Models
Ribosomal proteins (Rps) are essential for functional ribosomes, protein synthesis, and proliferative cell growth. Paradoxically, mutation of Rps can actually promote growth and proliferation and, in some cases, bestow predisposition to cancer. Our work provided the first rationale to explain the counter-intuitive organ overgrowth phenotypes observed for Drosophila Rp mutants by revealing that Rp mutants can drive tissue overgrowth cell extrinsically, whereby reduced Rps in the hormone-secreting gland of the larvae decreases activity of the steroid hormone ecdysone, extending the growth phase of development and causing tissue overgrowth. This project aims to extend these studies to better understand how Rp mutations cause the hypoplastic anemia associated with the human leukemia. Thus we have developed Drosophila models to specifically reduce Rps in the hematopoietic system to gain novel insights into how Rp mutations can promote leukemia in humans. This project will provide much needed insight into the processes linking reduced levels of Rps to cancer predisposition.
Project 4 - Cancer stem cell models
The discovery of cancer stem cells emphasized the importance of interactions between stem cells and their microenvironment. More than 2 decades of research in Drosophila have documented the capacity of the supporting cellular microenvironment or “niche” in orchestrating renewal and differentiation of stem cell populations. In the context of cancer, we expect proper organisation of the cellular microenvironment will also be essential for preventing tumour formation. However, this area of cancer biology has remained enigmatic due to the difficulty in tracing interactions between human tumours and their niche in mammals. This project will extend on our exciting observations that loss of the MYC repressor Hfp/FIR from the Drosophila ovarian stem cell niche generates germline tumours far from the local niche. We aim to extend these observations to human and mouse models to begin dissecting contributions of the tumour microenvironment to initiation and progression of ovarian cancer.
- Nick Lim#, Belal Shohayeb#, Olga Zaytseva, Naomi Mitchell, Marie Bogoyevitch, *Dominc Ng, and *Leonie Quinn, (# co-first, *co-senior). Glial-specific functions of microcephaly protein WDR62, and interaction with the mitotic kinase AURKA, are essential for Drosophila brain growth. Stem Cell Reports 2017 v9 (1), p32–41 (IF 7.338).
- Linna Guo, Olga Zaysteva, Zuqin Nie, Naomi C Mitchell, Jue Er Amanda Lee, Thomas Ware, Linda Parsons, Rodney Luwor, Gretchen Poortinga, Ross D Hannan, David L Levens, Leonie Quinn. Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the Mediator Complex to modulate MYC transcription and tissue growth. Nucleic Acids Research 2016 doi.org/10.1093/nar/gkw461 (IF 9.12)
- Nicole Dominado#, John E. La Marca#, Nicole A. Siddall, James Heaney, Mai Tran, Yu Cai, Fengwei Yu†, Hongyan Wang, W. Gregory Somers, *Leonie Quinn and *Gary Hime (# co-first author *co-senior and corresponding authors). Rbf regulates Drosophila spermatogenesis via control of somatic stem and progenitor cell fate in the larval testis. Stem Cell Reports 2016 7(6), 1152–1163. http://doi.org/10.1016/j.stemcr.2016.11.007 (IF 7.338).
- Naomi Mitchell, Elissaveta Tchoubrieva, Arjun Chahal, Simone Woods, Amanda Lee, Jane Lin, Linda Parsons, Gretchen Poortinga, Katherine Hannan, Richard Pearson, Ross Hannan and Leonie Quinn. Signalling to ribosomal RNA synthesis: MYC-driven rDNA transcription requires S6 Kinase. Cellular Signalling 2015 doi: 10.1016/j.cellsig.2015.07.018.
- Jue Er Amanda Lee, Naomi Mitchell, Olga Zaytseva, Arjun Chahal, Peter Mendis, Linda Parsons, Gretchen Poortinga, David Levens, Ross Hannan, and Leonie Quinn. Hfp-dependent transcriptional repression of dMYC is fundamental to tissue overgrowth in Drosophila XPB models. Nature Communications 2015; doi:10.1038/ncomms8404. [IF=10.742]
- Olga Zaytseva, Nora Tenis, Naomi Mitchell, Shin-ichiro Kanno, Akira Yasui, Jörg Heierhorst and Leonie Quinn. ASCIZ regulates development and mitosis in Drosophila as a conserved regulator of Cutup/dynein light chain. Genetics 2014; 196 (2): 443–53. doi:10.1534/genetics.113.159541.
- Poortinga, G., L. M. Quinn, and R. D. Hannan. 2014. Targeting RNA Polymerase I to Treat MYC-Driven Cancer. Oncogene 2014; (10) 1038/onc.2014.13.
- Jane Lin, Naomi Mitchell, Elly Tchoubrieva, Mary Stewart, Steven Marygold, Richard Pearson, *Leonie Quinn and *Ross Hannan. Drosophila Ribosomal Protein Mutants Control Tissue Growth Non-Autonomously via Effects on the Prothoracic Gland and Ecdysone. PloS Genetics 2011; 7 (12) e1002408 (*co-senior and corresponding authors)
- Naomi Mitchell, Timothy Johanson, Nicola Cranna, Amanda Lee, Helena Richardson, Ross Hannan and Leonie Quinn. Hfp inhibits Drosophila myc transcription and cell growth in a TFIIH/Hay-dependent manner. Development 2010; 137, 2875-2884.
- Adrian Monk, Nicole Siddall, Talila Volk, Barbara Fraser, Leonie Quinn, Eileen McLaughlin and Gary Hime. How is required for stem cell maintenance in the Drosophila testis and for the onset of transit amplifying divisions. Cell Stem Cell 2010; 6(4): 348-60.
- Naomi Mitchell, Nicola Cranna, Helena Richardson and Leonie Quinn. The Ecdysone- inducible zinc finger transcription factor, Crol regulates wg transcription and cell cycle progression in Drosophila. Development 2008; (featured on the front cover). 135(16): 2707-16.