Prof Joyce’s laboratory has developed a pioneering technology that allows scientists to visualise the tumour in living subjects in real-time. By employing these methodologies, Prof Joyce explores uncharted territory into how brain tumours evolve over time.

Currently, most brain cancer patients follow similar treatment plans. Identifying how a brain tumour evolves over time will improve our understanding of both what to treat and when to treat the cancer, offering opportunities to develop new therapeutic targets and treatment strategies.

Illuminating the brain tumour microenvironment: gaining new insights into gliomas through intravital imaging and molecular MRI

Brain tumours represent some of the most aggressive forms of cancer. The brain is our most critical organ, controlling every aspect of who we are as humans, and therefore brain tumours are also amongst the most feared of all cancers. Eighty percent of tumours that develop within the brain are gliomas, with over half being glioblastoma, the most malignant form of this disease. Unfortunately, despite treatment with standard of care therapy (surgery, radiation and temozolomide chemotherapy), glioblastomas are essentially incurable, and the 5-year survival rate for patients with the most aggressive gliomas remains <5%. This dismal clinical outcome underscores the urgent need for novel perspectives and effective therapeutic strategies to treat patients with this disease. We have been tackling this challenge in my lab for several years, and have taken the strategy of deeply exploring the brain tumour microenvironment (TME) as a means to exploit the knowledge we gain to develop new therapies. Since cancers and their TME are highly dynamic and co-evolve during tumour progression and in response to treatment, it is necessary to study cancer as it develops - in real time and in situ, in all its complexity. Therefore, my lab has now developed a strategy using the unique power of intravital microscopy (IVM) and molecular MRI to literally ‘look inside’ the brain of living animals in a longitudinal manner; a first in the cancer field.

In October 2022, Prof Johanna Joyce published results from the research supported by our grant in the prestigious journal of Science Translational Medicine. What she has discovered could change the landscape of how MRIs are done in the future as a central tool we currently use to diagnose brain cancer.

Publication

https://www.science.org/doi/10.1126/scitranslmed.abo2952 

Studying the tumour microenvironment in brain cancer is incredibly complex – there are few tools at hand and significant variation in current experimental models. This project has two key game-changing aspects: (1) to use artificial intelligence to analyse vast volumes of existing tumour images not easily capable by humans and (2) using a novel tool developed by Dr Gomez to re-create, cultivate and analyse the tumour in a 3D model called an organoid. This combination will enable Dr Gomez and his team to identify new therapies for brain cancer patients.

Few therapies are available and approved for use in brain cancer. By exploring a paradigm shifting approach to treating brain cancer, that is, to disrupt the tumour and it’s environment, this project will offer new treatments and strategies for brain cancer patients.

Harnessing artificial intelligence to develop new therapies for glioblastoma

While the survival rates of most cancers have dramatically improved in the last few decades, this is not the case for brain cancers, where the 5-year survival has hardly changed for 30 years, remaining around 20%. For glioblastoma, the most diagnosed malignant brain cancer in adults, the statistics are far worse, with a 5- year survival of just 5%. Despite recent advances in understanding some of the critical drivers of glioblastoma formation and progression, this knowledge has not yet translated into improvements in glioblastoma therapy. This lack of progress in the clinical setting is mainly due to the highly heterogeneous nature of glioblastoma and the ability of tumour cells to switch transcriptional programs in response to the interactions with cells in the tumour microenvironment, which leads to therapy resistance and tumour recurrence. Thus, targeting the interaction of tumour cells with non-malignant cells in the tumour microenvironment has recently emerged as an exciting anti-cancer approach in glioblastoma.

Scientists are starting to work out how the gut microbiome can affect brain health when just 6 years ago such a notion was laughable in the scientific community. If there is such a connection with the health of the gut and brain as well as in diseases such as Parkinson’s, MND and ALS; could there be such a link to causing, preventing or treating brain cancer? We will be the first to find out.

Causes of brain cancer remain largely unknown. There are also no known preventative measures. But if a microbe associated with brain cancer could be identified, and if we could prove that the product of that microbe was associated with GBM and show that it was having an effect on the tumour then removing the microbe could prevent tumour progression and help treat the cancer.

Developing a HTS platform in identifying microbiome-modulated small molecule impacts on multiple glioblastoma signalling pathways

Despite the advances in cancer research, glioblastoma multiforme (GBM) remains poorly understood and largely incurable, mostly, due to its intra- and inter- tumour heterogeneity. Mutations in specific genes are thought to be driving the development of GBM. However, most of these genes are only studied at the genomic level, with no deep investigation on how these mutations dysregulate the cellular signalling pathways. Therefore, a better understanding of the GBM molecular pathways, without disregarding inter-pathway impacts, will help in identifying cancer modulators with the potential to block these pathways to limit the tumorigenic abilities of GBM.

In the last few years, multiple studies have suggested a central role for the microbiome in modulating cancer initiation, progression, and treatment responsiveness. The microbiome consists of an ecosystem of indigenous microorganisms inhabiting on and within the human body surfaces (including the gut, oral cavity, vagina, and skin). Alterations in the habitual compositional structure of microbiome communities have been also associated with different diseases. Importantly, recent works demonstrate possible causal impacts of the microbiome on cancer-related phenotypes. Knowledge regarding the microbiome impacts on intracellular signalling events, and the associated cancer cell behaviour in glioblastoma remains elusive. Such causal understanding of host-microbiome modulatory activity on signalling pathways central to GBM development and clinical behaviour may hold promise in harnessing microbes and their secreted products into new biological therapies preventing and treating GBM.

In this proposed project, we aim to establish a high throughput screening pipeline enabling to massively screen thousands of microbiome-related, food-related and host-related molecules involved in the host-microbiome niche and their simultaneous effects on multiple key signalling pathways in human GBM. Using this innovative system, we aim to shed new light into the mechanisms orchestrating microbiome regulation of GBM formation and development and harness this molecular knowledge towards identification and experimentation in new microbiome-based modulators of GBM signalling and cellular activity. In short, our long-term objectives in this project include uncovering microbes and metabolites participating in the modulation of specific cellular events in tumour cells, impacting tumour development, and progression.

Never before has space biology been applied to brain cancer research. The team’s previous work has shown that other cancer cells at micro-gravity are unable to sense each other, no longer grow into tumours and die. The project will go a step further and in an Australian first, a research mission will launch brain cancer cells into space to orbit on the International Space Station to see if brain cancer cells can be killed at zero gravity and understand how that is happening.

While eventually brain cancer patients may be sent to space for treatment, the outcome is to develop drugs that patients can take while on Earth that tricks the brain cancer cells into behaving like they are in space.

Space microgravity to disrupt GBM mechanotransduction

Mechanobiology is the study of how cells are influenced by their physical environment. This emerging field of research provides an important perspective on understanding many aspects of cellular function and dysfunction.

Gravitational force is presumed to play a crucial role in regulating cell and tissue homeostasis by inducing mechanical stresses experienced at the cellular level. Thus, the concept of mechanical unloading (a decrease in mechanical stress) is associated with the weightlessness of space and can be replicated by simulating microgravity conditions, allowing for investigation of the mechanobiology aspects of cell function. The mechanical unloading of cells under microgravity conditions shifts the balance between physiology and pathophysiology, accelerating the progression and development of some disease states.

Cancer cells subjected to very weak gravity (microgravity) have been shown to have an altered cell cycle as well as a decreased migratory response. As such, microgravity has been thought to have anti-tumour potential through growth inhibition.

Previous groups have shown that microgravity inhibits proliferation and increases the chemosensitivity to cisplatin of malignant glioma. Thus, by subjecting glial tumour cells to microgravity, this project aims to further characterise the underlying fundamental molecular mechanisms that determine the aggressiveness of high-grade gliomas and identify novel therapeutic targets that are critical drivers of glioblastoma growth, highlighting a new direction and era for brain cancer therapies.

Dr Chou’s team built Australia’s first-ever microgravity device for looking at cancer cells. They have already shown that under microgravity, the most aggressive type of brain cancer is disrupted. The brain cancer is unable to form and stops growing.

Dr Chou has successfully built the world’s very first, fully functional brain tumour on a microchip. This ‘chip’ consists of multiple layers including a blood brain barrier, blood vessels and a 3D printed brain tumour. This has never been done before. Dr Chou was recently published about this in Advanced Therapeutics – you can read the publication below.

Dr Chou also discovered how to ‘open’ the blood brain barrier, to allow more drugs to get through to treat the brain cancer. His team is working on how to properly control and time this.

Publications

Silvani G, Basirun C, Wu H, Mehner C, Poole K, Bradbury P, Chou J. A 3D-Bioprinted Vascularized Glioblastoma-on-a-Chip for Studying the Impact of Simulated Microgravity as a Novel Pre-Clinical Approach in Brain Tumor Therapy. Advanced Therapeutics.2021;2100106. 

Silvani, G., Bradbury, P., Basirun, C. et al. Testing 3D printed biological platform for advancing simulated microgravity and space mechanobiology research. npj Microgravity 8, 19 (2022). https://doi.org/10.1038/s41526-022-00207-6

The power of the circadian rhythm in controlling how the body functions is just being understood. For example, it was only in 2017 that the Nobel Prize in Physiology went to scientists finding what controls the circadian rhythm. Now, only a few years later, we’re already taking this knowledge and seeing whether it’s the missing link in understanding why targeted treatments are not working in brain cancer.

Brain cancer is one of the best genetically mapped cancers but despite this, treatments targeting specific genes of the cancer have not worked. Perhaps it is not the failure of the treatments but the failure to give the treatments at the right time of day, where it will have the most impact and stop the cancer in its tracks.

The cancer clock is (not) ticking: how brain tumour hypoxia regulates circadian rhythms

Circadian rhythms are physiological, behavioural and cellular changes that follow a daily 24-hour cycle. These rhythms are encoded as a ‘molecular clock’ in the genome of nearly every cell of the body. Individual cells in the body are normally synchronised to the external time by a ‘master clock’ present in the suprachiasmatic nucleus of the brain. Clinical and laboratory-based studies have suggested links between disrupted cellular circadian clocks and brain tumour progression, but the mechanisms are poorly understood. It is vital that we understand how circadian rhythms affect brain tumour growth and progression, as they may be a novel anti-cancer strategy.

One proposed mechanism of circadian control is through tumour hypoxia (low oxygen). Hypoxia is common in high-grade brain tumours, particularly glioblastoma, due to rapid cell proliferation. Both hypoxia and circadian disruption are associated with aggressive behaviour in brain tumours. Furthermore, hypoxia can ‘reset’ circadian rhythms and tumours may use this to control circadian and oncogenic pathways.

This project aims to understand how hypoxia can alter circadian rhythms to increase brain tumour progression, with the goal of identifying whether the circadian rhythm can be used to synchronise brain cancer cells to a time of day where they are most vulnerable to attack through new drug targets.