Some bacteria, viruses and fungi are like unwelcomed guests who crash a party and cause trouble. Without an invitation, they discreetly slip into the body where they cause an infection that damages tissues and threatens a person’s health.
Luckily, the body is staffed with immune cells—known as neutrophils—responsible for removing these party crashers. Neutrophils have several tactics at their disposal to eliminate microscopic invaders, including the release of neutrophil extracellular traps (NETs). NETs are web-like structures of DNA and proteins that bind, disarm and kill invaders.
“Although NETs are a powerful weapon in the fight against infections, accumulating evidence suggests that NETs might also contribute to the spread of a cancer to other sites in the body,” says Dr. Scott Bratman, a Scientist at the Princess Margaret Cancer Centre.
Recently, Dr. Bratman and his colleagues published a report describing a series of experiments that helped clarify the importance of NETs in this process.
They discovered that high blood levels of toxic molecules known as reactive oxygen species (ROS) triggered the release of NETs from neutrophils in the absence of microscopic invaders. They also found that NETs accumulated in the lungs more than in any other organ.
Next, the researchers examined how high ROS levels and NETs effected experimental models of breast cancer, and head and neck cancer. They found that when ROS levels were high, both cancers were more likely to spread to the lungs.
The researchers also obtained evidence suggesting that this phenomenon occurs not only in experimental models of cancer, but also in cancer patients. ROS levels were found to be much higher in head and neck cancer patients whose cancer eventually spread to their lungs.
Commenting on his findings, Dr. Bratman says, “We found that cancer can spread to the lungs by using NETs released in response to high ROS levels. Because of this, we believe that ROS could represent a new and promising anticancer target that could help stop the spread of cancer.”
This work was supported by The Terry Fox Foundation and The Princess Margaret Cancer Foundation. M. Ikura holds a Tier 1 Canada Research Chair in Cancer Structural Biology.
Inoue M, Nakashima R, Enomoto M, Koike Y, Zhao X, Yip K, Huang SH, Waldron JN, Ikura M, Liu FF, Bratman SV. Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis. Nat Commun. 2018 Nov 30. doi: 10.1038/s41467-018-07550-x.
Patients in need of an organ transplant wait eagerly for news that a suitable organ has been found, but ultimately not every organ from every donor can be used. Donor lungs have one of the lowest utilization rates, and as a result one in five patients in need will die waiting for a lung transplant.
One of the challenges is assessing the health and quality of a donor lung, and deciding if it is suitable for transplantation. That decision today rests on an assessment by the surgeon—a process that currently relies on ‘qualitative’ or subjective factors.
To help improve how lungs are assessed, SQI Diagnostics, a life sciences company based in Toronto, is partnering with Dr. Shaf Keshavjee and the world-renowned Toronto Lung Transplant Program at UHN. The partnership will enable the development of a device that can better inform whether a lung is suitable for transplantation, by using measurable biological readouts of lung health.
The partnership builds on work at UHN that was funded in part by Genome Canada to identify biomarkers that accurately predict the health of donor lungs and patient outcomes following transplant. SQI will bring its expertise in developing point-of-care devices to create a multiplex test sensitive to protein biomarkers predictive of lung health, with a rapid time-to-result that is critical to the lung transplant decision-making process.
Andrew Morris, CEO of SQI Diagnostics says, “This agreement represents a reputational landmark for SQI, given the pioneering and global leadership role of Toronto and UHN in the growing field of lung transplantation. It also represents a major long-term commercialization opportunity. SQI’s multi-array testing is proving to be applicable in areas well beyond drug development and disease identification.”
UHN’s Technology Development and Commercialization Office negotiated the research and licensing agreements and will help ensure that the long-term commercialization opportunity is realized.
“Integrating rapid diagnostics is a major step forward in lung transplantation. By providing transplant teams with quantitative metrics to more accurately assess donor lungs, we are moving decision making in transplantation into the era of personalized medicine,” says Dr. Keshavjee.
To learn more, see the press release.
This work was funded by the Government of Canada through Genome Canada and Ontario Genomics (OGI-6427).
Stay warm this winter while showing the world that you are proud to be part of Canada’s largest research hospital—where science, research and learning converge to improve health care.
To reserve your Research at UHN jacket, email www@uhnresearch.ca by March 6, 2019 with your name, contact details and order details (number of jackets and sizes).
Jackets are $45 each, inclusive of tax and shipping, and available in a variety of sizes (Women XS to 3XL; and Men S to 5XL—see sizing charts below).
These three-layer bonded softshell jackets are black in colour and feature an embroidered ‘Research at UHN’ logo in white, gold and blue. They are made of anti-pill microfleece and are stretchable, waterproof, wind resistant and fully breathable.
Thousands of people at UHN are involved in research and are committed to accelerating discovery and innovation. Wearing a ‘Research at UHN’ jacket is one small way to show others that we are in it together to achieve our aim of A Healthier World.
Why do females take longer to recover from concussions than males?
A team of researchers led by Dr. Angela Colantonio, Senior Scientist at KITE (formerly Toronto Rehabilitation Institute), has found a possible explanation: females are more likely to sustain a neck injury at the time of a concussion.
Concussions are the most common type of mild traumatic brain injury sustained by Canadians. However, the condition is not very well understood. Researchers have only recently begun to uncover the differences between the sexes in response to concussions.
To better understand these differences, Dr. Colantonio’s team examined the health records of over 90,000 female and male patients admitted to an emergency department in Ontario with a mild concussion.
“Females have more distinct and weaker necks which increases the risk of sustaining a neck injury along with a concussion. We suspected that additional neck injuries may contribute to why females take longer to recover,” describes Dr. Colantonio.
In analyzing the health records, the research team found that females with concussions were more likely to experience neck injury than males.
“Neck injuries can be missed during an initial screening in the emergency department because they have similar symptoms as concussions, such as dizziness, unsteadiness and headaches,” explains Dr. Colantonio.
“This research contributes to our understanding of how concussions may be experienced differently by the sexes which informs better care and prevention of injury.”
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the US National Institutes of Health, the Canadian Institutes of Health Research, the Alzheimer’s Association and the Toronto Rehab Foundation.
Sutton M, Chan V, Escobar M, Mollayeva T, Hu Z, Colantonio A. Neck Injury Comorbidity in Concussion-Related Emergency Department Visits: A Population-Based Study of Sex Differences Across the Life Span. J Womens Health (Larchmt). 2018 Dec 28. doi: 10.1089/jwh.2018.7282.
A new program to support breast cancer survivors
Coping with cancer and receiving treatment can leave patients scarred and emotionally drained. Having lived through a combination of surgery, chemotherapy and radiotherapy, survivors often grapple with cancer’s emotional toll long after their physical recovery.
“Breast cancer survivors may have lost one or both of their breasts, have residual scars or swelling, and start menopause prematurely,” describes Dr. Mary Jane Esplen. “These effects often cause survivors to experience grief, lowered self-esteem and confidence, and shame about the appearance of their body.”
To improve the emotional well-being of breast cancer survivors, Dr. Esplen developed a program called Restoring Body Image after Cancer (ReBIC).
The program consists of eight group sessions where participants are encouraged to generate a series of images in their mind’s eye. These exercises help them to express their personal identity and self-image difficulties and to work through them. Factors that promote a negative body image and feelings of shame are also discussed.
In a study completed by Dr. Esplen to evaluate the impact of ReBIC, participants reported improvements in body image, their quality of life and ability to manage breast cancer-related symptoms. In light of its success, ReBIC is now being offered at University Health Network.
EsplenMJ, et al. J Clin Oncol. 2018 Mar; 36(8):749-756. Supported by the Canadian Breast Cancer Foundation (now part of the Canadian Cancer Society) and the Canadian Breast Cancer Research Alliance.
Performance Upgrade for Immune CellsEnhancing immunotherapy to treat a variety of cancers
When it comes to self-improvement, we have all sorts of tools at our disposal: glasses to improve our vision, treadmills to help us stay fit, and vaccines to ward off infectious diseases.
A research team led by Dr. Naoto Hirano has engineered a molecule with the potential to enhance the effectiveness of our immune system against cancer.
Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy currently approved in the United States to treat blood cancers. It involves extracting immune cells from the patient, genetically engineering them to recognize cancerous cells, and infusing them back into the patient where they are able to target and kill cancerous cells.
“The CAR molecule enables immune cells to recognize cancerous cells,” explains Dr. Hirano.
“We have engineered an improved CAR molecule
that imparts greater potency to immune cells against different cancers, including solid tumours, and showed that it did not worsen any potential side effects in experimental models.”
Future work will focus on validating these findings and translating them into clinical trials to improve the safety and efficacy of the CAR T cell therapy.
Kagoya Y, et al. Nat Med. 2018 Mar; 24(3):352-359. Supported by Canadian Institutes of Health Research (CIHR), the Ontario Institute for Cancer Research, BioCanRx, Japan Society for the Promotion of Science, the Government of Ontario, the Natural Sciences and Engineering Research Council of Canada (NSERC), Takara Bio Inc. and The Princess Margaret Cancer Foundation (PMCF).
ittle Changes that MatterA single DNA letter variation in the genome can impact cancer risk
Just as a snowfall atop a mountain can mark the beginning of an avalanche, a single, often innocuous event can mark the beginning of a catastrophe.
Some of the most devastating cancers can also have an unremarkable beginning. Dr. Hansen He has discovered just such a seemingly innocuous event.
Tracing back the progression of prostate cancer, Dr. He and his team discovered that varying a single letter in an individual’s genetic code can increase the risk for a more aggressive form of prostate cancer.
“We found that this particular genetic variation is not in a functional region of the genome—such as a region that contains instructions for building cellular machinery or for housekeeping activities,” says Dr. He.
“Rather, it was in a region of the genome considered to have no useful information.”
“We need more studies at the genome level to understand how these single genetic variations can change the way cells regulate their activity,” adds Dr. He. “Then we can evaluate how they change the risk for cancer and take steps to prevent them from worsening outcomes.”
Hua JT, et al. Cell. 2018 Jul 26; 174(3):564-575.e18. Supported by NSERC; CIHR; the Movember Foundation; Prostate Cancer Canada; the U.S. Department of Defense; The Terry Fox Research Institute; the Ministry of Economic Development, Job Creation and Trade; and PMCF.
Immune cells in the heart work hard to eliminate viruses that damage heart muscle
Have you been sick with a cold recently? That sore and scratchy throat is caused by infection with a cold virus, which is typically eliminated by the immune system in a week or so.
In some cases, however, cold and other viruses can infect the heart, which could lead to much more serious consequences. Viral infection can cause myocarditis, inflammation of the heart muscle that can compromise its ability to pump blood. Little is known about how the immune system plays a role in this disease.
To address this gap in knowledge, Dr. Slava Epelman led a study to examine the role of dendritic cells, a type of immune cell, in viral myocarditis. His research team found that at least five types of dendritic cells reside in the heart, where they trigger immune responses to help eliminate infections.
The team noted that the two most abundant types of dendritic cells in the heart were crucial for eliminating viruses that infect the heart. The absence of these cells not only dampened the anti-virus response, but also led to significant heart damage that impaired the organ’s pumping action—an early warning sign for heart failure.
These results suggest that dendritic cells are important gatekeepers of heart health: they quickly eliminate viral infections before the infections can cause full-blown heart failure. Understanding the role that these immune cells play in this process could help with the development of new therapies to treat heart infections.
Clemente-Casares X et al. Immunity. 2017 Nov 21;47(5):974-989. Supported by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation, the March of Dimes Canada, the Ted Rogers Centre for Heart Research, the Heart & Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, the Peter Munk Cardiac Centre, the National Institutes of Health and the Toronto General & Western Hospital Foundation (TGWHF). M Cybulsky holds a Tier 1 Canada Research Chair (CRC) in Arterial Wall Biology and Atherogenesis.
Treatment for Two HIV drugs alter levels of a hormone that is critical to a healthy pregnancy
A healthy pregnant woman translates to a healthy baby. This is the reason that many women go to great lengths to improve their health once they become pregnant.
But as Dr. Lena Serghides discovered in two studies, women who are infected with the human immunodeficiency virus (HIV) face greater challenges when trying to ensure the health of their babies.
HIV-positive pregnant women are advised to take a drug regimen—commonly referred to as combination antiretroviral therapy (cART)—to prevent mother-to-child transmission of the virus. Unfortunately, these drug regimens are often associated with a number of adverse birth outcomes, including preterm delivery and low birth weight.
To better understand how these treatments affect birth outcomes, Dr. Serghides and her research team measured the levels of several different hormones in pregnant women, before and after they were randomly assigned to take two different cART regimens.
Her team found that levels of the hormone estradiol were decreased in women taking one type of cART regimen and increased in those taking the other. These changes were linked to significantly lower birth weight, suggesting that hormonal changes may contribute to the adverse birth outcomes for women taking cART.
Says Dr. Serghides, “The results of our study underscore the need for more research on the long-term effects of these regimens as they may affect fetal development by differentially altering hormone levels.”
McDonald CR et al. Clin Infect Dis. 2018 Jan 18;66(3):428-436 & Balogun KA et al. Clin Infect Dis. 2018 Jan 18;66(3):420-427. Supported by CIHR; the Ontario HIV Treatment Network G655; the Canadian Foundation for AIDS Research; the Global Alliance to Prevent Prematurity and Stillbirth; and Grand Challenges in Global Health: Preventing Preterm Birth Initiative. KC Kain holds a Tier 1 CRC in Molecular Parasitology.
Tools of the TradeA new method enables scientists to better control the production of cell types
Jack of all trades, master of none. It can be nice to have many skills, but sometimes it’s better to focus on building expertise in one key area.
The same may be true when developing cell therapies with iPS and iPL cells, as Dr. Thomas Waddell and his graduate student Li Guo found. iPS cells are stem cells that can be used to make a wide variety of cell therapies; however, their use is limited because they could grow into unwanted cell types, including tumours.
To address these limitations, the research team (along with Dr. Andras Nagy from the Lunenfeld-Tanenbaum Research Institute) used an approach called ‘interrupted reprogramming’ to make iPL cells. In contrast to iPS cells, iPL cells can be coaxed into becoming only a restricted number of different cell types, depending on the type of cell that was used to make the iPL cell.
This method makes it easier to control which cell types can be produced and to create batches of cells that are more pure.
To explore the potential use of iPL cells to treat respiratory disease, the research team focused on a type of cell—known as a club cell—that is found on the inner surface of the lungs. They used their approach to convert club cells into iPL cells; then, they coaxed the iPL cells into becoming other types of lung cells, such as goblet cells, which produce a thick fluid that traps foreign substances in the lungs.
This method could be used to develop new cell-based therapies to speed up the healing process after lung injury or to repair donor lungs before transplantation.
Guo L et al. Stem Cell Reports. 2017 Dec 12;9(6):1780-1795. Supported by the Hospital for Sick Children Transplant and Regenerative Medicine Program, CIHR, the Ontario Research Fund and TGWHF. TK Waddell holds the Pearson-Ginsberg Chair in Thoracic Surgery and the Thomson Family Chair in Translational Research. A Nagy holds a Tier 1 CRC in Stem Cells and Regeneration.
Findings published in Cell have revealed that a rarely studied type of genetic material—known as circular RNA—is prevalent in prostate cancer and some of this genetic material is essential for growth of the cancer.
The work was carried out in the labs of Drs. Housheng Hansen He at the Princess Margaret Cancer Centre and Paul Boutros at the University of California, Los Angeles (formerly at the Ontario Institute of Cancer Research).
“Novel sequencing approaches have opened up a new realm of research. By studying this circular genetic material in prostate cancer, we’ve uncovered a wealth of insight into how the cancer grows and spreads, while uncovering potential new strategies to target and kill it,” says Dr. He, lead author of the study.
The main type of genetic material in the cell—known as genomic DNA—serves as the ‘source book’ that holds the information required by cells to carry out chemical reactions required for life. DNA is also used by the cell to create or ‘code for’ other forms of genetic material, including RNA, which is thought of as the ‘working copy’ of the genetic code.
Much of the DNA and RNA found in the cell resembles a string or rope of varying lengths; however, some of it can be joined end to end to create a circular molecule.
Dr. He and his collaborators began to suspect that circular RNA may be important for prostate cancer growth because previous studies have suggested that various distinct forms of RNA are present in prostate cancer cells. As well, circular RNA has been implicated in other types of cancers, such as colon and breast cancer.
The researchers used a technique known as ultra-deep sequencing to define the circular RNA present within 144 tumours from patients with prostate cancer. They identified over 76 thousand circular RNAs—more than 30 thousand of which had not been previously described.
The researchers then compared the genetic data to patient outcomes, revealing that tumours from individuals with the most aggressive types of prostate cancer tended to have aberrant production of circular RNAs.
The researchers took this work one step further by targeting and inhibiting specific circular RNA molecules in experimental models of prostate cancer. They found that around 11% of the circular RNA was important for driving cancer growth—emphasizing its potential to serve as a new anticancer target.
This work was supported by the Princess Margaret Cancer Foundation, the Princess Margaret Genomic Centre, the Ontario Institute for Cancer Research, Prostate Cancer Canada, Terry Fox Research Institute, the Canada Foundation for Innovation, the Ontario Research Fund, the Natural Sciences and Engineering Research Council of Canada, the Canadian Cancer Society, the Canadian Institutes of Health Research, the Shanghai Committee of Science and Technology, University of Toronto and The Center for Translational Molecular Medicine.
Chen S, et al. Widespread and Functional RNA Circularization in Localized Prostate Cancer. Cell. 2019 Feb 7. doi: https://doi.org/10.1016/j.cell.2019.01.025.
