Pancreatic cancer is the deadliest form of cancer affecting Canadians: according to the Canadian Cancer Society, 93% of patients succumb to the disease within five years of their diagnosis. In light of these dismal statistics, researchers are working tirelessly to develop more effective treatments for the disease.

UHN Affiliated Scientist Dr. Senthil Muthuswamy and his collaborators, including Drs. Maria Cristina Nostro and Gordon Keller, have developed a new experimental model of pancreatic cancer that could provide patients with more personalized treatments and improved health outcomes.

The new model consists of three-dimensional clusters of cells derived from patient tumour samples, which can be cultured and grown in the laboratory. The researchers found that these clusters preserve many of the physiological features of the original tumour, recapitulating aspects of a patient's disease phenotype more accurately than other culture models currently available. In particular, the researchers found that clusters originating from different tumours displayed differential sensitivity to an anti-cancer drug.

These findings suggest that tumour cell clusters could be used for personalized drug screens to identify the most effective treatment regimen for each patient's pancreatic cancer. However, larger and more rigorous studies are needed before this strategy can be incorporated into clinical practice.

This work was supported by the Ontario Institute for Cancer Research, the Canadian Cancer Society, the Campbell Family Institute for Breast Cancer Research, the Ontario Ministry of Health and Long-Term Care and The Princess Margaret Cancer Foundation. C Arrowsmith and G Keller hold Tier 1 Canada Research Chairs in Structural Proteomics and in Embryonic Stem Cell Biology, respectively.

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Huang L, Holtzinger A, Jagan I, BeGora M, Lohse I, Ngai N, Nostro C, Wang R, Muthuswamy LB, Crawford HC, Arrowsmith C, Kalloger SE, Renouf DJ, Connor AA, Cleary S, Schaeffer DF, Roehrl M, Tsao MS, Gallinger S, Keller G, Muthuswamy SK. Nature Medicine. 2015 November. doi:10.1038/nm.3973. [Pubmed abstract]

2015 has been a productive year for McEwen Centre Researchers. Congratulations to all for receiving prestigious awards, bringing in new grants and publishing in high impact journals. Listed below are some of the outstanding achievements from this past year:

Stem Cell Biology

In two Nature Biotechnology articles, Dr. Gordon Keller advanced the state of regenerative medicine research for arthritic and liver diseases. The first study showed that TGFb signalling promotes the development of articular chondrocytes—the cells responsible for generating joint cartilage. This study was the first to delineate the signalling molecules that govern the production of chondrocytes in vitro. The second study revealed a new method to produce cells, known as cholangiocytes (which line liver bile ducts) from human pluripotent stem cells. This method represents a new model system that researchers can now use to better understand why cholangiocytes malfunction in bile duct disorders, such as cystic fibrosis.

Drs. John Dick and Norman Iscove, revealed that a protein called CDK6 helps regulate how often hematopoietic stem cells (HSCs) divide. Manipulating CDK6 levels in HSCs may improve current methods for generating HSCs for use in the clinic (Cell Stem Cell).

A study by Dr. Nostro provided a strategy for generating highly enriched populations of human pluripotent stem cell-derived pancreatic progenitor cells. The findings will advance research on the pathways that regulate the maturation of functional pancreatic beta cells and inform the development of new treatments for beta cell disorders like diabetes (Stem Cell Reports).

Dr. Peter Zandstra identified a new marker that can track the different cell populations that are generated when somatic cells are reprogrammed to become pluripotent stem cells (Nat Commun). The marker, which is known as CD24, provides a more accurate map of the reprogramming process that will help unlock the clinical potential of the different cell populations that arise.

In a paradigm-shifting study published in Science, Dr. Dick showed that blood production in adults occurs through a two-tier process. The results of the study challenge the current multi-stage model of blood production and provide a more accurate roadmap of blood cell development that will help us to better understand a wide variety of human blood disorders.

Cancer

Dr. Dick developed a humanized experimental model of acute myeloid leukemia (AML) and used it to demonstrate that the protein IKAROS, which is not functional in a small fraction of AML patients, has the ability to inhibit the growth of leukemia cells (Leukemia). The findings are evidence that this new experimental system is an excellent model for studying AML.

Neural Repair and Regeneration

A study by Dr. Freda Miller, published in Developmental Cell, revealed for the first time that mutations in the Ankrd11 gene may contribute to the development of autism spectrum disorder. The results provide new insight into normal neuronal development as well as disorders associated with aberrant positioning of neurons.

Dr. Michael Fehlings initiated a study to evaluate the potential use of human neural stem cells to treat chronic spinal cord injury. Of the 12 study participants who received the cells, seven had sustained improvements in sensory function. A larger clinical trial is now underway to determine whether these stem cell treatments can improve motor function in patients with more severe spinal cord damage.

Drs. Molly Shoichet and Derek van der Kooy used a hydrogel—made of a blend of hyaluronan and methylcellulose—to enhance the delivery and function of transplanted adult stem cell progeny in the central nervous system. The researchers demonstrated that using this hydrogel improved the ability of stem cells to restore vision loss and treat neurological disorders (Stem Cell Reports). Dr. Shoichet used the same hydrogel to enhance the delivery of cyclosporin A, a drug that promotes the development of neural stem/progenitor cells, to the brain. The hydrogel and drug formulation enhanced the differentiation of these stem cells into neurons, which suggests that it may provide a safe and effective method for promoting brain repair (J Control Release).

Drs. Andras Nagy and Cindi Morshead tracked the migration, growth and differentiation of neural stem cells (NSCs) after stroke-induced brain injury. The team found that NSCs migrate to the site of damage where they give rise to cells known as reactive astrocytes. The astrocytes form scar tissue as part of the wound healing process and can be coaxed into becoming neurons. An understanding of the factors that promote this process will help us to develop novel regenerative strategies to repair the stroke-injured brain (Cell Stem Cell).

Angiogenesis

Dr. Ren-Ke Li discovered that boosting levels of a protein known as Canopy2 in the heart stimulates the growth of new blood vessels. These findings suggest that Canopy2 could be used to increase blood supply to the injured heart as a potential therapy for heart failure (Eur Heart J).

McEwen Centre Researchers performed exceptionally in Canadian Institutes of Health Research grant competitions, garnering a combined total of more than $10.3 million. These funds will be used to develop new mechanisms for rebuilding damaged neural circuitry (Miller), uncover new applications for biomaterials in medicine (Shoichet), develop methods for promoting cardiac regeneration (Li) and study cellular reprogramming (Nagy).

In the past year, researchers at the Centre also secured more than $121 million in federal and provincial funding to build new private sector collaborations and translate promising stem cell discoveries into more effective therapies for patients. This includes funding from the Ontario Research Fund Research Excellence Program, which will enable Dr. Li to partner with Create Inc. to develop new stem cell-based methods for treating heart disease. An investment from Genome Canada that will support a partnership between Dr. Keshavjee and Lung Bioengineering Inc. to develop a genomic-based test that is aimed at increasing the number of donor lungs available. Also, $114 million from the Canada First Research Excellence Fund, which will fund Medicine by Design, a multi-institutional stem cell research initiative led by Dr. Zandstra, that will support the research programs of various McEwen Centre Researchers (Keller, Keshavjee, Shoichet and van der Kooy).

Researchers at the McEwen Centre also excelled in the recent Ontario Institute for Regenerative Medicine grant competitions. Funding received will be used to develop: dynamic platforms for modelling lung disease (Waddell), novel stem cell approaches for regenerating injured spinal cords (Fehlings), methods to repair white matter in the brain following disease or injury (Miller), stem cell-based therapies for regenerating the heart (Laflamme) and tools to improve the therapeutic effects of stem cells (Nagy).

With additional funding from several charitable foundations and institutions, McEwen Centre Researchers will be able to develop new treatments for spinal cord injury (Krembil Foundation, Fehlings); age-related macular degeneration (Foundation for Fighting Blindness; Nagy), cancer (Terry Fox Research Institute; Dick and Iscove), leukemia (Leukemia & Lymphoma Society of Canada; Iscove), heart disease (Heart and Stroke Foundation; Li) and lung disease (Canadian Cystic Fibrosis Foundation; Keshavjee).

Finally, two Canada Foundation for Innovation awards secured by research teams at UHN will provide vital infrastructure for McEwen Centre Researchers who are working to increase the availability and quality of donor organs (Keshavjee) and find new therapeutic strategies for diabetes (Cattral, Gaisano, Nostro).

The McEwen Centre wishes everyone Happy Holidays
and all the best for 2016!