How growing human mini-livers may reveal valuable clues to curing liver cancer

Minderoo Foundation proudly supports the Liver Cancer Collaborative, for which more than 50 multidisciplinary experts in Australia and Asia are building a globally unique biorepository and dataset with extensive clinical and genomics data from diagnosis to late-stage disease. Dr Benjamin Dwyer leads the patient-derived organoid platform for the Collaborative.

Bringing together bioengineering with clinical and genomic liver cancer research, Dr Dwyer’s ground-breaking multi-disciplinary work aims to improve outcomes for the 3,000 people diagnosed with the disease across Australia each year.

Q: Growing a human mini-liver in a lab – when did this become possible and how are you doing it? How will patients benefit from this approach?

A: In the past decade there have been many exciting developments in the field, including organoids (which recreate 3D liver structure, function and disease pathology in vitro), slice cultures (thin sections of liver tissue maintained in the lab for up to 2 weeks), organ on a chip and microfluidic models (which allow elements of cellular spatial patterning and fluid flow to be modelled). We grow 3D organoid models in the lab from patient tumour and surrounding non-tumour liver tissue. We characterise these cells by their marker expression, genetic makeup and RNA expression and match this back to the original tumour to understand how well our cell culture model reflects the tumour tissue from which they were derived. Doing this allows us to be more confident when we test patient-specific responses to drug treatments. Using our drug screening results, we hope to repurpose and develop new therapies, matched back to patient subtypes using this platform.

Q: What are precision bioprinted organoids and how do they help scale up drug screening? What types of therapeutics are you testing?

A: One of the limitations of traditional organoid culture is that the standard supportive matrix the organoids are traditionally grown in doesn’t recreate some of the elements of the environment present in a liver tumour, such as stiffness. These elements can affect responses to therapeutics. We need to be able to model this in the lab so our results will more accurately reflect what may happen in a patient. To do this, we collaborate with an Australian company, Inventia Life Sciences, who produces the RASTRUM bioprinter. The RASTRUM enables us to bioprint our models in specialised bio-inks where we can adjust properties such as stiffness and molecular makeup to be more like the tumour environment in the liver, in a highly standardised way. We can bioprint thousands of small 3D tumour models in an automated, programmable, and reproducible way, which allows us to look at thousands of different drugs at once in organoid models grown from different patients.

At present, we are testing a library of 1,600 drugs that have already been approved for use in patients, which will provide a benchmark to test new types of therapies. We hope to identify drugs not previously used for liver cancer patients that could be clinically tested in this platform. Because they are approved for use in patients, this will significantly shorten the time to go from bench to bedside.

We are also conducting in-depth image-based phenotypic analysis of our organoids. Our aim is to generate a library of images which can be analysed by other researchers with their own unique pipelines to generate further insights.

Q: What are the benefits of this approach over more traditional preclinical models of cancer?

A: Each model has its specific strengths and weaknesses, and together they can bridge the gap between the laboratory and how therapies will respond in patients.

Although fast and cheap to use, traditional 2D cell culture models do not recreate the 3D environment of the patient.

Organoid models allow us to model drug responses, in a high throughput, patient-specific way in a 3D environment approximating the patient, allowing greater confidence bringing forward positive ‘hits’ to be tested in patients. With the recent announcement from the US FDA that animal models are no longer required for drug approvals, the development of in vitro systems that can accurately reproduce the tumour environment, such as our organoid platform combined with the power of precision bio-printing, represent a scientific and regulatory keystone for developing new treatments for cancers.

Additionally organoid systems have potential use in the future as ‘mini clinical trials’ in the dish to inform treatment decisions by assessing many different drugs or drug combinations in a high throughput way. Using this information for a clinician to make an informed and personalised choice about which treatment combination is best for a patient to improve disease outcomes.

Q: How does your organoid platform integrate and support the work of the Liver Cancer Collaborative, for instance the work of clinician and biobank lead Dr Michael Wallace and genomics lead Dr Ankur Sharma?

A: The organoid platform provides functional data to integrate with clinical data collected by Dr Michael Wallace, and multi-omics data generated by Dr Ankur Sharma’s team. Although we can make inferences about the biology underpinning responses to therapies and predict which patients will respond to therapies, our organoid platform provides a robust system to evaluate these predictions. Although each platform is valuable in isolation, the power of the Liver Cancer Collaborative is the combination of diverse types of matched data from the same patients over time to provide a complete overview and hypothesis testing pipeline to fully understand the complexities of liver cancer and provide actionable solutions.

Q: Given the Liver Cancer Collaborative is collecting and interpreting large amounts of data generated from de-identified patient biosamples, how will this information be shared with the research community to inform better treatment options?

A: The Liver Cancer Collaborative has partnered with the Perkins Cancer Biobank to collect and analyse tumour samples and has established a game changing digital research environment (DRE), to help generate and manage a rich source of integrated data about liver cancer patients. The DRE is a secure, online, collaborative space that enables members of the Collaborative to easily share, integrate and analyse data, as we work together towards developing a precision approach to treating liver cancer.

Additionally, de-identified data from the Liver Cancer Collaborative will be made available to the global research community and connected to other liver cancer patient data through Minderoo Foundation’s Federated Cancer Data project, which is championing a federated approach to cancer data sharing whereby data stay at their original location and are connected and analysed remotely without copying or transfer.

Q: Minderoo’s Collaborate Against Cancer initiative is focused on strong collaborations across borders and disciplines, breaking down barriers and unlocking data siloes. How is the Liver Cancer Collaborative working to strengthen collaboration so that your research will benefit as many patients with liver disease as possible?

A: We are actively engaging with clinical, academic and industry partners to ensure the samples and data collected will have the greatest utility for liver cancer patients. We have a large Australian and international network, which we have strengthened through our monthly liver interest group meetings where we invite prominent speakers alongside members of our Collaborative to share insights and discuss critical issues in liver cancer research.

We are especially interested in academic and industry partners who would be interested in assessing their new therapeutics drugs for liver cancer patients via our organoid platform.

Q: On a personal note, what attracted you to the field of regenerative medicine and a scientific career more generally, and who were your mentors?

A: I have always been fascinated by the ability of tissues and organs to regenerate and have had a long interest how and why this occurs. As a student, Professor George Yeoh at University of Western Australia was instrumental in fostering that curiosity and passion for science.

One of my most important career mentors has been Professor Nina Tirnitz-Parker. In our earlier days when I was just starting out and she was a senior member of the Yeoh lab, she was one of the most thorough and talented scientists I’ve worked with and taught me so much at the lab bench. As her career has advanced to forming her own lab, I’ve learned a lot about people management and the huge value of collaboration in science, and she has been instrumental in both my move to Edinburgh and returning home with the Liver Cancer Collaborative.

Q: What are some interesting facts you can share with us about the liver?

A: The liver is an extraordinary organ. It performs about 500 different functions, from drug processing to producing molecules that aid digestion. It is also the only human organ that is able to regenerate itself. As well as containing a stem-like cell population, located in the bile ducts, that can regenerate liver tissue during conditions of severe and chronic injury, the hepatocytes (the main epithelial cell type of the liver) are capable of remarkable expansion. Tests in mice showed that hepatocytes are capable of at least a 7.3 x 1020-fold expansion, which makes their regenerative capacity similar to blood stem cells.

Q: How excited are you about the impact your work is likely to have?

A: I am extremely excited about the potential impact we might have for patients with liver cancers, as well as having the opportunity to develop solutions to some of the challenges of liver cancer organoids. We are in a unique position within the Liver Cancer Collaborative of having diverse and internationally leading expertise in liver biology and medicine, fantastic industry partners and have unparalleled access to patient tissues for our work. Although we are excited, we are also focussed on achieving the outcomes of this project to ultimately make life better for the patients that so generously provide us with tissues in difficult circumstances.

For more information, visit the website of the Liver Cancer Collaborative