University of Queensland (UQ) researchers based at TRI are unlocking the secrets of melanoma cells to identify potential new drug targets and personalised treatment regimens for patients with the skin cancer, melanoma. 

Collaborating with Queensland University of Technology (QUT) mathematicians including Professor Matthew Simpson, Professor Haass and his team recently debunked the longstanding ‘grow-or-go’ theory that melanoma cells only have enough energy to either proliferate (grow) or metastasize (go). Using both laboratory studies and mathematical modelling, the researchers proved that melanoma tumour cells can actually do both at the same time.

“This discovery might have an impact on patient treatment,” said Professor Haass.

“There has been concern that using a drug to stops the tumour from growing might cause the cancer cells to switch and begin metastasizing. Once the initial drug activity wanes, tumour cells that have migrated may start to grow and generate metastatic disease.

“Now we know that this isn’t necessarily the case, however, this may differ from drug to drug.”

The finding was part of the laboratory’s work on understanding the biology of melanoma cells.

Melanoma tumours can contain numerous cells with not only different genetic mutations, but also dynamically different behaviour, according to Professor Haass.

“Most people think of a melanoma tumour as a big chunk of cells that are all the same, but this isn’t the case. Within tumours, there are different clusters of melanoma cells sitting next to each other.

“Each cluster can respond very differently to the drugs used to treat melanoma. A drug might kill one cluster, while another one continues to grow or even grow faster as the competition with the other cluster is gone.

“If we can identify these different clusters in a patient, we can help clinicians determine the best combination and timing of drugs to treat the melanoma.”

The team is using real-time imaging of melanoma cells in 3D culture and in vivo, to investigate the role of these subpopulations. With this method, they can colour code the different behaviour of the cells and watch them moving around the in the tumour.

They are the only group in Australia and one of the few groups internationally who are using this sophisticated technology.

It has enabled them to identify potential new markers for drug therapies and potential new targets to use in simultaneously targeting differential subpopulations.

Professor Haass is also looking at how melanoma cells interact with the surrounding microenvironment—that is the extracellular matrix, blood vessels, immune and blood cells. He believes we could harness this microenvironment to stop melanoma cells from growing and invading other parts of the body.

“One of my postgraduate students has a cool study that shows the melanoma cells can get stopped by the microenvironment under certain conditions. They can’t squeeze through,” said Professor Haass.

“We are looking at this phenomenon to see if we can manipulate melanoma tumours to prevent their growth and spread.”

In addition to these studies, Professor Haass and an industry partner are investigating a possible way to enhance melanoma immunotherapy, using patients’ blood samples before and after treatment.

In Australia, melanoma is the third most commonly diagnosed cancer, accounting for more than 13,000 cases in 2016 and more than 1700 deaths.[1] If caught early, the cancer is usually curable. In many cases, however, the cancer has advanced and begun metastasizing or spreading to other parts of the body before diagnosis. By this point, the cancer can be difficult to cure.

About Professor Haass

Dr Nikolas Haass is a Professor at The University of Queensland Diamantina Institute/Translational Research Institute and Adjunct Faculty member at the Centenary Institute, University of Sydney. After obtaining his PhD at the German Cancer Research Center, University of Heidelberg, he trained as a dermatologist, with a focus on skin cancers, at the University Hospital Hamburg-Eppendorf, Germany. He then spent five years at the Wistar Institute/University of Pennsylvania, Philadelphia, as a post-doctoral fellow funded by the German Research Foundation. As a Cameron Melanoma Research Fellow from October 2007 to February 2013, he headed the group ‘Experimental Melanoma Therapy’ at the Centenary Institute. In March 2013, he commenced his current position at UQDI.

Research projects

• Defining the role of Microphthalmia-associated Transcription Factor (MITF) in melanoma growth by real-time cell cycle imaging
• Modulating phenotypic melanoma heterogeneity and lymphocyte infiltration to improve both targeted and immune therapy
• Migrastasis: Altering cell mechanics to inhibit melanoma cell migration, invasion and metastasis
• Mathematical modelling of cell proliferation and invasion with fluorescent cell cycle indicators
• Induction of immunogenic cell death to improve melanoma immunotherapy
• Assessing the effect of molecule X on immune cell function for patients receiving melanoma immunotherapy
• Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy

Recent journal publications on this body of research 

Chauvistré H, Daignault SM, Shannan B, Ju RJ, Picard D, Vogel FCE, Egetemaier S, Krepler C, Rebecca VW, Sechi A, Kaschani F, Keminer O, Stehbens SJ, Váraljai R, Ninck S, Liu Q, Yin X, Jeyakumar K, Xiao M, Löffek S, Kubat L, Spassova I, Gul S, Rahmann S, Horn S, Ehrmann M, Paschen A, Becker JC, Helfrich I, Rauh D, Kaiser M, Remke M, Herlyn M, Haass NK, Schadendorf D, Roesch A., “The Janus-faced role of KDM5B heterogeneity in melanoma: differentiation as a situational driver of both growth arrest and drug-resistance”, bioRxiv, 1 April 2020. doi: 10.1101/2020.04.01.999847  [A collaboration between University of Duisburg-Essen, Germany, The Wistar Institute, Philadelphia, USA, and the UQDI at TRI.]

Gavagnin E, Vittadello ST, Gunasingh G, Haass NK, Simpson MJ, Rogers T, Yates CA “Synchronised oscillations in growing cell populations are explained by demographic noise.” Preprint published in bioRxiv, 13 March 2020; doi: 10.1101/2020.03.13.987032. [A collaboration between University of Bath, QUT and UQDI.]

Vittadello ST, McCue SW, Gunasingh G, Haass NK*, Simpson MJ* “A novel mathematical model of heterogeneous cell proliferation.” Preprint published in arXiv, 6^th March 2020; doi: https://arxiv.org/abs/2003.03024 *equal contribution

Guo D, Beaumont KA, Sharp DM, Lui GYL, Weninger W, Haass NK*, Tikoo S* “Abrogation of RAB27A expression transiently affects melanoma cell proliferation.” Preprint published in bioRxiv, 8^th April 2020; doi: 10.1101/2019.12.27.889329 *equal contribution & corresponding authors [Dr Shweta Tikoo is a Post-Doc from Prof Haass’ previous lab in Sydney and co-supervises PhD student Dajiang Guo.]

Henser-Brownhill T, Ju RJ, Haass NK, Stehbens SJ, Ballestrem C, Cootes TF (2020) “Estimation of cell cycle states of human melanoma cells with quantitative phase imaging and deep learning.” Proc IEEE Int Symp Biomed Imaging, 2020: 1617-1621

Vittadello S. T., McCue S. W., Gency G., Haass N., Simpson M.J., “Examining go-or-grow using fluorescent cell-cycle indicators and cell-cycle-inhibiting drugs”. Biophysical Journal, 2020;118 6: 1243-1247. doi:10.1016/j.bpj.2020.01.036

Vittadello S. T., McCue S. W., Gency G., Haass N., Simpson M.J., “Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation”, Journal of The Royal Society Interface, 2019;16 157: 20190382. doi:10.1098/rsif.2019.0382

Guo D., Lui G.Y.L., Lai S.L., Wilmott J.S., et al., “RAB27A promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes”, International Journal of Cancer, 2019;144: 3070-3085. doi:10.1002/ijc.32064

Guo D., Tikoo S., Haass N.K., “RAB27A-mediated melanoma exosomes: promoters of invasion and metastasis”, Translational Cancer Research, 2019;8(3): 732-735. doi:10.21037/tcr.2019.04.25

Emran A.A., Chinna C., Brinda R., Ahmed F., Hammerlindl H., Huefner A., Haass N.K., Schuehly W., Schaider H., “Magnolol induces cell death through PI3K/Akt-mediated epigenetic modifications boosting treatment of BRAF- and NRAS-mutant melanoma”, Cancer Medicine, 2019;8(3): 1186-1196. doi:10.1002/cam4.1978

Simpson M.J., Jin W., Vittadello S.T., Tambyah T.A., Ryan J.M., Gunasingh G., Haass N.K., McCue S.W., “Stochastic models of cell invasion with fluorescent cell cycle indicators”, Physica A: Statistical Mechanics and its Applications, 2018;510:375-386. doi:10.1016/j.physa.2018.06.128

Ju R.J., Stehbens S.J. and Haass N.K., “The role of melanoma cell-stroma interaction in cell motility, invasion, and metastasis”, Frontiers in Medicine, 2018; 5:307.