Glioma has one of the poorest cancer prognoses – a statistic that several research groups across the globe are working to change. One key approach is the development of suitable models for assessing the efficacy of novel therapeutics; something that Christian Naus, Professor at The University of British Columbia (BC, Canada) and Canada Research Chair in Gap Junctions in Neurological Disorders, is currently working on. But with a challenge on this scale, collaboration is key: Christian is working with colleagues across disciplines and drawing on additive manufacturing expertise to develop 3D glioma models with the hope that these 3D organoids will facilitate personalized medicine approaches to one of the brain’s most significant threats.
We met Christian at SfN’s Neuroscience 2016 (San Diego, CA, USA, 12–16 November 2016) where he presented his recent research and spoke about his hopes for the use of 3D printing and personalized medicine in glioma research and treatment.
Please could you tell us a little about your background and current work?
My research program explores the role of gap junction channels and their proteins (connexins and pannexins) in disease, including consequences of mutations on gap junction structure and function, and the role of these intercellular channels in diagnosis of disease and development of novel therapeutic strategies. My lab has conducted over 25 years of research in neurobiology and cancer, focused on cellular and molecular studies to characterize the role of gap junctions in proliferation, differentiation, transgenic mouse models of neurological disorders, and preclinical therapeutic studies for cancer, stroke and Alzheimer’s disease.
You recently presented you group’s work, ‘Modeling glioma using 3D bioprinting’, at Neuroscience 2016 – could you give an overview of this?
This work is a collaborative project with my research associate Wun Chey Sin (University of British Columbia), and colleagues from Cyfuse Biomedical KK (Tokyo, Japan), specifically Kaori Harada and D Song.
Malignant glioma is an aggressive cancer originating in the CNS with very poor prognosis and a median survival of about one year. The current standard for care is surgical resection, adjuvant chemotherapy and radiation therapy. Most cancer treatments aim to kill tumor cells by taking advantage of their accelerated growth. However, gliomas almost always return due to survival of invading glioma cells, often arising in a region proximal to the primary tumor site.
Approaches to study human gliomas vary from in vitro culture conditions to establishing tumors in vivo in animal models. We have previously demonstrated that the loss of connexin43-mediated intercellular communication in U118 human glioma spheroids increased their invasiveness on a fibronectin substrate . In order to better understand how loss of connexin43 will affect glioma growth, invasion and recurrence in a multicellular environment, we used a bioprinting system (Regenova Bio-3D Printer, Cyfuse Biomedical KK) to generate human neural organoids consisting of iPSC-derived neurospheres printed with the “Kenzan” method.
After culturing the neurospheres in chambers for several weeks, individual cellular spheroids merged to simulate an in vivo neural microenvironment. Human glioma cells grown as spheroids were implanted into this organoid. Tumor growth can be readily assessed in this system, as well as quantification of glioma cell invasion into the surrounding neural tissue, as detailed in our previous study . This platform provides a unique tool to manipulate the glioma microenvironment and assess the efficacy of various therapeutics.
What are the main challenges involved in modeling glioma progression?
Despite significant advances in biomedical and life sciences research, translational bottlenecks are limiting the availability of new therapeutics that are urgently needed to treat glioma.
“A key bottleneck is the lack of relevant and predictive tools to identify the best drug candidates for use in humans.”
A key bottleneck is the lack of relevant and predictive tools to identify the best drug candidates for use in humans. Currently, early-stage testing of drugs relies on the screening of therapeutic candidates on various types of cells in culture and on the testing in animal models of human disease. Neither approach is able to accurately predict outcomes in clinical trials because they fail to recapitulate the disease condition in humans. Cell cultures are grown in a 2D environment and lack a tissue-like (i.e., 3D) environment, while animal models have significant biological differences from humans. As such, development of new drugs is expensive, slow and seldom successful – resulting in increasing drug development costs and thereby higher drug prices.
We are pursuing 3D tissue innovations that will improve the efficiency and pace of drug discovery. 3D Bioprinting is a revolutionizing process that involves tissue fabrication by using 3D printer technology to create 3D living structures replicating the cellular and matrix architecture of specific tissues and organs of the body.
How could this new approach impact patients in the future?
“[3D bioprinting] provides a highly context-specific human platform to test and validate therapeutic treatments in a timely and affordable manner.”
The emergence of 3D bioprinting is revolutionizing the field of therapeutic discoveries. This process involves tissue fabrication, using printer technology to create 3D living structures replicating the cellular and matrix architecture of specific tissues and organs of the body. This provides a highly context-specific human platform to test and validate therapeutic treatments in a timely and affordable manner. As a result, the insights that are gained through the use of 3D bioprinting could translate quite well to the clinic, enabling the realization of practicing personalized medicine. For example, 3D bioprinted replicas of an individual’s disease (e.g., glioma) could be tested for drug suitability, combinatory treatments and efficacy. In this way a therapeutic can be specifically matched to the unique features of an individual’s disease.
Finally, what was your highlight of Neuroscience 2016?
My highlight of Neuroscience 2016 was the experience of presenting new approaches to study human glioma with a realistic translational aspect. Partnering with Cyfuse Biomedical, who also attended SfN as an exhibitor, provided a unique opportunity to highlight our glioma research as a strong collaboration between academia and industry. I look forward to additional interactions of this nature to optimize the clinical application of our research.
- Qurratulain A, Sin W-C, Naus CC. Reduction in gap junction intercellular communication promotes glioma migration. Oncotarget 6(13), 11447–11464 (2015).
- Sin WC, Aftab Q, Bechberger JF, Leung JH, Chen H, Naus CC. Astrocytes promote glioma invasion via the gap junction protein connexin43. Oncogene 35(12), 1504–1516 (2016).
You can find more interviews and news from Neuroscience 2016 here.