At the cutting edge of cancer
Image: Professor Jennifer Stow (centre) and colleagues in the ACRF Cancer Biology Imaging facility.
Earlier this year, The University of Queensland, Australia, opened a $2.3 million Cancer Ultrastructure and Function Facility to drive cancer treatments forward.
Funded by the Australian Cancer Research Foundation and home to a wealth of cutting-edge imaging and microscopy equipment, CUFF is set to provide unprecedented insight into cancer cells in action.
"This is all about giving us a better understanding of how cancer cells behave in tumours from patients, as well as in experimental models, so we can better design drug treatments," highlights Professor Jennifer Stow, Deputy Director of Research at the UQ Institute for Molecular Bioscience, home to the new facility.
"The facility will allow us to perform genotype-phenotype correlations at new levels of resolution, speed and in multi-dimensions using samples from patients, model organisms and organoids," she adds. "Working with teams of biologists, clinicians and chemists based at IMB and throughout UQ, [these new resources] will help us to understand cancer processes, define patient-derived cancer mutations and develop targeted therapies."
3D reconstruction of Melanoma Spheroid.
IMB's existing ACRF Cancer Biology Imaging facility, which opened in February 2010, already hosts an array of high-end confocal and epi-fluorescence microscopes. However the latest facility adds a Leica SP8 STED3X confocal microscope, a 3i lattice light sheet microscope and a Thermo Fisher VolumeScopeSEM.
According to Stow, the STED microscope enables super resolution analysis of molecular interactions in cancer cells, so IMB researchers can now interrogate receptor signalling pathways, and specialised signaling membrane domains, such as caveolae and macropinosomes.
"For example, one aim of this work is to define oncogene-driven signalling that can be targeted with new or existing drugs to block cancer growth," she says.
And while light and electron microscopy correlative microscopy is already being implemented at IMB, Stow reckons the STED could be used as part of a STED-TEM set-up.
"We've got a few groups looking at correlative imaging with our existing microscopes, but potentially this can also be carried out with STED," she says. "This is going to be increasingly important as we try to integrate all our imaging from whole animals to cellular levels and down to the molecular level."
Meanwhile, having access to lattice light sheet microscopy opens the door to rapid live cell imaging with high spatial and temporal resolution. As Stow puts it: "This is just fantastic for looking at very rapid cell behaviours and events on or near the cell surface."
Cancer cells imaged using lattice light sheet microscopy.
Stow and fellow researchers will use the instrument to interrogate cell behaviours over time in culture and in organoids or model animals such as zebrafish.
"It is already being used to investigate immune cell and cancer cell interactions and responses in cancer cells expressing mutated genes, under different metabolic conditions and after treatment with drugs," she adds.
Cancer cells imaged using lattice light sheet microscopy.
In addition to the STED and lattice sheet microscope, Stow is very excited about the VolumeScopeSEM, which will be used for serial block face SEM and 3D ultrastructure of cancer cells, organoids, tumours and cancer cells in situ.
"We can reconstruct cells and tissues in 3D, to map cell organelle changes and investigate cell-cell interactions and cell-microenvironment interactions in tumours," she says. "Several investigators are growing tumours as organoids.... and we can look at the architecture of cells here, in 3D environments, before and after treatments."
Stow also reckons the serial block face SEM will find new applications. "It will be nice to move this beyond plain ultrastructure and into labelling structures too, to localise proteins," she says. "I really do think that this is where this technology will move and we'll be working on this in the future."
Lattice light sheet microscopy at the new ACRF facility captures cancer cells.
In addition to CUFF's latest instruments, the imaging equipment at the IMB and the wealth of electron microscopes in the Center for Microscopy and Microanalysis, the University of Queensland is home to other intensive imaging facilities, sited across several centres.
The Queensland Brain Institute has many super-resolution imaging techniques while the Translational Research Institute - dedicated to translating research into medical practice applications - houses automated slide scanning and microscopes for large-scale sampling.
"We have a good collaborative environment across the whole University," says Stow. "Investigators can use the instrument they need, staff are ready to help and dedicated experts at each site are there, working at the cutting-edge of these technologies and ensuring users are upskilled."
Imaging aside, the CUFF's $2.3 million ACRF grant has also been used to part-fund a Dell r740 and nVIDIA V100 GPU-based supercomputer, to manage the facility's growing data deluge. As imaging methods ranging from volume electron microscopy to lattice sheet microscopy advance, vast datasets on the terabyte scale are generated.
"Having the computer infrastructure to handle the necessary image processing, deconvolution and storage is critical," points out Stow. "So an important part of what we have set up at the university is the computer infrastructure we need to handle big data. "
Indeed, the researcher points out how advances in instrumentation have outstripped the development of analytical software. "We've got this new-found ability to produce huge amounts of image data but we now need the usable software programs to analyse it," she asserts. "We really need to adapt our computing ability to take full advantage of the information we are generating."
Researchers are already placing block-face scanning data on public databases, such as the Zooniverse for the general public to analyse. Stow reckons lattice lightsheet imaging data will follow this trend soon, although new collaborations with software developers will be crucial for the future of big image data analysis.
"IMB is already working with software companies informally but I would also like to see new start-ups and developers populating this space to make collaborations more accessible," says Stow."We will see more and more software distributed as open source... and I think there is going to be a lot more international collaboration generated around image analysis and processing."
And looking to the future, clinical collaboration is also going to be key. Key chief investigators on the University of Queenland's ACRF grants are clinicians, and right now, Stow and many colleagues are working with clinicians on model systems. However Stow is keen to see these interactions grow.
"We want to start looking at a wide range of patient samples which isn't really happening at the moment," she says. "But this will soon change when we have the genotype-phenotype correlations for individual patient samples being generated on these high-end microscopes; then we can really gain comprehensive understanding about what's going on in individual tumours."
"This is where the field is going and we're now very much set up for this," she adds. "And given this, I am hopeful that we are increasingly going to have a direct impact on actual patient treatments."