Content warning: mentions of suicide.

After a month of moustache-growing to raise awareness for men’s health, ‘Movember’ has come to an end. What started in Australia in 2003 as a charity campaign, Movember has since expanded internationally with a larger focus on prostate cancer, testicular cancer, and mental health and suicide prevention. 

Movember aims to destigmatize the conversations surrounding men’s health. It’s simple to participate in the movement: just grow a ‘mo’ — a moustache. 

University of Toronto faculty and students shared their experiences with the movement and their stories of personal purpose and growth — all while showing off their top-notch moustaches that have grown alongside them.

Maximilian Casuba

Maximilian Casuba is a U of T student studying political science and history. He hopes to go to law school after graduating, but is keeping his options open.
DINA DONG/THE VARSITY

The beard and moustache have been part of Maximillian Casuba’s regular look since he was in ninth grade, so it’s nothing new. Casuba’s Movember routine consists of a little bit of shampoo when he showers, or just a splash of water. He shaves off his neckbeard and trims his facial hair as needed. 

However, his experience with Movember goes beyond just participating in the movement. Casuba lost his father to liver cancer last year, and dedicates his mo to his father every year. Last Movember, Casuba let his beard grow freely to commemorate the passing of his father, who first taught him to shave his peach-fuzz in seventh grade.

DINA DONG/THE VARSITY

Casuba expressed that although dedicating a month to raise awareness on men’s health is great, he wants to remind us that cancer is a year-round problem. According to the Canadian Cancer Society, cancer is the number one leading cause of death in Canada.

DINA DONG/THE VARSITY

“Cancer should be acknowledged year round,” Casuba said. “I think it’s nice to hear that there’s this one month dedicated to it too, especially November because it’s bloody cold outside. We have this little scarf,” he explains while pointing at his beard.

Mado Ghazal 

Mado Ghazal is a Rotman Commerce student. Ghazal shares his experience growing up in Lebanon, Dubai, and Toronto, all of which shaped his understanding and meaning of men’s health and masculinity.
DINA DONG/THE VARSITY

Mado Ghazal’s moustache routine is easy. He conditions and brushes it with a special moustache brush. Facial hair is nothing new to him, but the length is. 

Ghazal has a personal connection to Movember, as his grandfather was a victim of prostate cancer. However, the month also means more to him beyond prostate cancer: Ghazal wanted to emphasize that it is also dedicated to raising awareness around mental health — a commonly overlooked problem amongst men. 

According to the Public Health Agency of Canada, the suicide rate among men is three times higher than women. That being said, it does not mean that other individuals are not prone to experiencing similar struggles with their mental health. 

DINA DONG/THE VARSITY

Ghazal believes that a contributing factor to the statistic is the ‘male archetype’ that men have to uphold. Growing up, Ghazal felt pressured to obtain the ‘typical’ muscular male body. “I was super skinny and I went through a lot of mental hurdles to actually look in the mirror to say this is okay,” he shared. 

“I’m not at where I want to be right now, and this is fine.” 

“There’s a lot of… physical standards that men are held up to that affect them,” he continued. “Body image issues, [they’re] not just something that’s faced by women; [they’re] something faced by everybody.”

DINA DONG/THE VARSITY

In addition to aesthetics, he discussed the social status that men are expected to achieve in Dubai, where he used to live: the “stereotypical ‘breadwinner’ social norm for men,” where all men are expected to work. If he isn’t working, then “it’s considered weird in the society [that Ghazal] grew up in.” 

He believes that one of the important conversations we should have is men’s health and masculinity. He noted, however, that this is not a matter of men’s health being “more important,” but rather working together with other societal issues to come up with better solutions through open-minded conversations.

Professor Charlie Keil 

Charlie Keil is a professor at the Department of History and Cinema Studies Institute, and he has been the Principal of Innis College for five years. DINA DONG/THE VARSITY

Professor Charlie Keil usually keeps a clean-shaven face, so the moustache is quite foreign to him in November. Although he’s not fond of it, he knows that it is for a good cause. His care routine is quite simple: he doesn’t have one. Keil reminds himself that the mo is not necessarily meant to be aesthetically pleasing. 

Keil has been participating in Movember for a couple of years now. Since he is currently teaching a larger full-year course, he decided to take the opportunity to raise awareness and money through his students. 

DINA DONG/THE VARSITY

The professor has been highlighting to his students that Movember is a time to raise awareness about mental health. Keil, although he is no expert, mentioned that there are barriers to men seeking help for mental health because of the social norms of masculinity. 

The American Psychological Association (APA) published a podcast explaining that a correlation exists between ideas of masculinity and the likelihood of men reaching out for support. Although masculinity norms are relative to different cultures, societies, and situations, some norms expect men to restrain from expressing their emotions, which in turn prevents them from seeking help. 

The APA recently released a new set of guidelines for psychological practice with boys and men. Although males “tend to hold privilege and power based on gender, they also demonstrate disproportionate rates” of issues, ranging in areas such as mental and physical health problems.

Through Movember, Keil hopes to liven this conversation among his students because he believes that everyone can play a part in the discussion on mental health. “The university has the greatest responsibility, because it’s the custodian of the students who are here, and the well-being of students is the university’s top priority,” Keil said. “But I think we all need to… [help] to ensure that the mental health of all the students is as well maintained as it can be.” 

DINA DONG/THE VARSITY

Professors need to be aware of their actions, and administrators need to make their best efforts, but Keil also emphasized that students need to play a part as well. He believes that “we all need to be cognisant” — students need to be aware of their own mental health as well as that of their peers. 

He continued on to explain that sometimes reaching out will have a positive effect “because part of [the problem] is isolation and not feeling connected.”

“If this can do a little bit toward helping raise that issue with students, then it’s totally worth the 30 days of bristliness,” he concluded, pointing at his moustache. 

Andrew Paul Raya 

Andrew Paul Raya graduated from U of T, where he specialized in psychology. Raya is currently taking non-degree courses related to social work and sexual diversity studies at the University of Toronto and York University. Raya is genderqueer, and prefers he and him or they and them pronouns. DINA DONG/THE VARSITY

While facial hair is widely associated with masculinity relative to cisgender men, Andrew Paul Raya does not see his facial hair as a representation of his gender identity. However, for November, he believes that the moustache is important to help raise awareness.

Raya has been participating in Movember since he was a teenager, when he would grow a goatee every year. Raya’s routine is simple but comes with challenges due to his sensitive skin. Aside from a little bit of hot water on the areas where he is going to shave, Raya uses nothing else to maintain his Movember look.

DINA DONG/THE VARSITY

Raya is currently the president of the St. Michael’s College LGBTQ+ group, which he founded with his fellow executives. He is also involved in a male-identifying ally work group at York University, which focuses on challenging “toxic masculinity,” the behaviour expected by males where they appear strong and expressionless. Through this work, he is trying to destigmatize gender stereotypes and emphasized that masculinity does not always have to be ‘toxic.’

On the topic of masculinity, Raya expressed that when he was using only he and him pronouns, he found that being masculine meant being strong, showing little emotion, and engaging in sports. Raya noted, however, that these are traits that “don’t exactly define a gender.”

Today, Raya believes that masculinity is defined by what someone believes it to mean. “If you feel comfortable calling yourself masculine, [then] that’s what really matters at the end of the day,” he said.

DINA DONG/THE VARSITY

In addition to challenging gender stereotypes, Raya also hopes that through his moustache, he can remind people that cisgender men are not the only ones affected by the illnesses that Movember brings awareness to, such as prostate and testicular cancer. “There are individuals who don’t use he and him pronouns but are also affected.” he said. “Men alone don’t have moustaches.” 

“Cancer doesn’t have a face, it doesn’t have a gender,” he continued. Movember, to Raya, is also a time to remind people that there are individuals — regardless of their identity or gender — that are being affected by cancer.

“Movember is a cause,” he said, “not just an image.” 

If you or someone you know is in distress, you can call:

• Canada Suicide Prevention Service phone available 24/7 at 1-833-456-4566
• Good 2 Talk Student Helpline at 1-866-925-5454
• Ontario Mental Health Helpline at 1-866-531-2600
• Gerstein Centre Crisis Line at 416-929-5200
• U of T Health & Wellness Centre at 416-978-8030.

Warning signs of suicide include:

• Talking about wanting to die
• Looking for a way to kill oneself
• Talking about feeling hopeless or having no purpose
• Talking about feeling trapped or being in unbearable pain
• Talking about being a burden to others
• Increasing use of alcohol or drugs
• Acting anxious, agitated, or recklessly
• Sleeping too little or too much
• Withdrawing or feeling isolated
• Showing rage or talking about seeking revenge
• Displaying extreme mood swings

The more of these signs a person shows, the greater the risk. If you suspect someone you know may be contemplating suicide, you should talk to them, according to the Canadian Association for Suicide Prevention.

Trillions of microorganisms are scattered throughout the human body, outnumbering human cells by a ratio of 10 to one. These living creatures have become an emerging target for cancer treatment.

In a recent U of T-affiliated review, scientists from the Princess Margaret Cancer Centre and the University Health Network have explored research on the complex relationship between the human microbiome and cancer. 

What is the human microbiome?

The human microbiome is the collection of genomes present in the microbes that live on or in humans. These microbes include not only bacteria, but also fungi, viruses, and prokaryotes, wrote Dr. Brian Coburn, a co-author of the study and a professor at U of T’s Department of Laboratory Medicine & Pathobiology.

Most microbes are concentrated in the genital tract and mucosal surfaces, which are the membranes that cover internal organs and various body cavities. A human’s microbiome develops from birth and is influenced by the mother’s microbiota, as well as individual genetic makeup and environmental exposure. 

The microbiome has been suggested to be directly causing cancer through inflammation of mucosal surfaces, systemic impairment of metabolism and the immune system, and influencing the effectiveness of anti-cancer therapy.

Certain bacterial species have been identified as more abundant in patients that respond to certain types of anti-cancer therapies than others, explained Coburn.

Researchers have also found that many tissues have their own distinct bacterial, viral, and fungal populations. Cancerous tissue itself appears to have an altered microbiome. Further evidence shows differences in the microbial composition of specific cancers. For example, scientists have found distinct microbial composition patterns in subtypes of breast cancer.  

How the microbiome could be a target for anti-cancer therapies

Positive responses to anti-cancer therapy are typically “defined by a reduction in the size of their tumor of 30% or more,” wrote co-author Dr. Aaron Hansen, an oncologist at the Princess Margaret Cancer Centre, to The Varsity. “This is a desirable outcome for treatment. Patients who do not respond to therapy typically have a growth of the tumor by 20% or they develop new metastasis.”

Metastasis is the growth of cancer at a secondary site, away from the initial location of cancer. 

Emerging evidence has also described tumour activity as closely related to abnormal microbiota in adjacent tissues. Scientists have suggested that microbiota may cause inflammation ⁠— or altered inflammatory signaling ⁠— in these tissues, which could promote the growth and spread of tumors. However, more research on tissue samples from cancerous and non-cancerous patients is needed to validate the results.

Scientists are looking at ways to manipulate the microbiome in humans, and often use animal subjects to test their hypothesis. These continue to be an important but imperfect tool for testing research hypotheses for human diseases.

“There is some evidence from observational studies and animal models that the gut microbiota is associated with response to some cancer therapies,” wrote Coburn, “but causality [sic] in humans is a difficult thing to definitively prove and this remains an untested hypothesis.”

Probiotics have been considered as a form of additional treatment for approved cancer therapies. In research involving mice, scientists have shown that probiotic supplementation could decrease the number of tumour cells and their proliferation.

Other researchers have found that the introduction of the bacteria Lactobacillus to mice decreased tumour size and improved survival rates, suggesting that altering the microbiome may have an impact on suppressing tumour growth.

The lasting challenge of research in this field

Research in this field has proven challenging because individuals vary in their responses to antibiotics, probiotics, and other interventions that affect the microbiome. There is a wide range of different types of probiotics, noted Coburn, and they can have vastly different effects on different patients, or they can have no effect at all.

“We don’t know what to use, how much, when or for how long and in which patients – it remains a very large research challenge [that] will take decades to thoroughly investigate,” he explained.

Furthermore, animal models “will always be limited in how they are applied to human disease and treatment,” he wrote. “In the end, only human studies (especially randomized controlled trials) can prove or disprove that a new type of therapy is safe or effective.”

Research on the effect of the microbiome on cancer is relatively new. Well-designed, controlled, and structured observational and interventional studies would shed light on this growing field. Such studies would enable clinicians to assess the link between the microbiome and cancer, as well as the microbiome’s potential in cancer diagnosis and treatment.

New research, wrote Coburn, could help clinicians “determine if the relationship is causal or simply coincidence and whether [the microbiome] is a useful therapeutic target.”

A new tumour analysis technique has been created to tackle the most common type of pancreatic cancer, in a new U of T-affiliated study. This method could improve physicians’ ability to better predict how a patient will be affected by the cancer, as well as reduce the health care costs of this type of analysis.

The researchers investigated pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related deaths in the world. It is predicted by scientists that PDAC could become the second leading cause of death by cancer by 2030.

The current system for analyzing tumours is flawed

Physicians currently use a three-tiered grading system to analyze tumours from PDAC. The system relies on the classification of tumours into three groups: well, moderate, and poorly differentiated.

The best tumours for pathological analysis are well differentiated, while the worst are poorly differentiated, according to Dr. Sangeetha Kalimuthu, an Assistant Professor at U of T’s Department of Laboratory Medicine & Pathobiology, in an interview with The Varsity.

Tumours in the middle of the scale are considered moderately differentiated. “Think of a well-formed ice cream,” she continued. “When it starts to melt, it gets all ugly and not really pretty to look at, so that’s in essence how a tumour behaves.

But a major problem with this current grading system is that most tumours from PDAC are identified as moderately differentiated. Tumours with this classification are of limited clinical utility, explained Kalimuthu, as they provide little useful prognostic information about the patient.

Recently, large–scale studies have identified prognostically significant molecular subtypes in PDAC. Different subtypes of PDAC are associated with differing clinical outcomes.

However, direct identification of a patient’s molecular subtype of PDAC through molecular analysis is expensive and not readily available worldwide. 

New study offers cost-effective solution for overcoming limitation

The U of T-affiliated study, co-authored by Kalimuthu, identified specific structural — or morphological — patterns in PDAC tumours and presented a novel tumour classification system based on these patterns.

The new classification system presented in the paper correlates morphological patterns with the known subtypes of PDAC. This enabled physicians to identify the molecular subtype of PDAC without using costly molecular analysis.

Kalimuthu added that looking at tissue stains “is the standard bread and butter of pathology.”

“Taking a tiny piece of tissue that you get from a much larger tumour and sequencing it doesn’t give you a representation of the tumour,” she said.

“We look at these stains so we can actually get an idea of the tumour — nothing [such as other techniques like sequencing] gives you a better picture of [it].”

Future potential to integrate technique with artificial intelligence

An established procedure that provides precedent for this newly developed classification system for PDAC tumours is an existing grading system for prostate cancer tumours.

Researchers devised the system, called Gleason grading, in 1966. It similarly gave prognostic information for colon cancer patients.

Kalimuthu and her co-authors hope that their new tumour grading system can fulfill a similar role for PDAC.

In the future, Kalimuthu and her co-authors hope to validate the PDAC-based grading system with a larger cohort of pathologists, before incorporating the grading system into a clinical setting.

If they can achieve this, the improved system of prognosis could help guide physicians in developing treatment plans for patients with PDAC.

Since the new classification system is based on patterns, Kalimuthu believes it could one day be integrated with artificial intelligence.

“This classification system could be directly applicable with deep learning algorithms — so that’s the long-term goal.”

What does scientific discourse have to do with artistic expression? For a research team at the Princess Margaret Cancer Centre, the answer is “everything.”

We once thought of our right and left brains as separate forces responsible for logical and creative thought, respectively. But scientific progress has shown us otherwise, as mental processes require that the whole brain works together in harmony to approach a task.

Just as the corpus callosum brings our hemispheres together as a band of nerve fibres, so too should science and art harmonize — so believes Dr. Mathieu Lupien, a Senior Scientist at the Princess Margaret Cancer Centre. 

Lupien incorporates art into his professional sphere to generate creative discourse between his close-knit team of researchers. He offers a unique approach to team-building by inviting his team to take a stroll through the Art Gallery of Ontario.

Each team member takes the time to walk through and choose a piece of artwork that speaks to them. Lupien then has the team come together as a group to share their chosen piece and engage in dialogue about what inspired them.

“I get to see the world from their perspective and they get to see mine from theirs,” said Lupien in an interview with The Varsity. The process helps the researchers better understand how they see the world through different lenses.

Lupien expresses that this is an exercise in using something creative, like art, to share who we are as scientists. It gives the team a glimpse into each other’s worlds. For example, if a member really enjoys the intricate detail in a piece, we can understand that the fine details they reflect in their own work are something they value. This helps us interpret the work they do in a more meaningful way.

“Our imagination is the only way to explore the unknown,” said Lupien. “We are working in uncharted territory sometimes, so creating an environment that is conducive to open, creative thought is important for our work.”

This slideshow requires JavaScript.

How can students integrate art and science into their own research methods?

Lupien describes that translating scientific works in an intelligible way is an art in itself. Science, technology, engineering, and mathematics can be highly complex areas, full of jargon which can be intimidating for many students interested in the field. Using creative expression is one way to translate complexities in an imaginative way.

He demonstrates this idea in his description of his research on epigenetics: the study of how the activity of our genes can change, without changing our DNA sequences. He describes the genome as six billion letters of DNA that form words that are different in nature. When they are organized into sentences, each of them tells a unique story.

In order to form specific parts of our body, such as muscle and brain tissue, we organize our genome, represented here as letters, in different ways to create distinct sentences. The folding process is guided by epigenetic events, or post-it notes, which highlight the regions of our genome that need to be read.

Perhaps we can say that art relates in the same way. Each stroke of the brush or strike of the pen creates a unique image, and the artist goes over certain areas of the painting with these tools to highlight parts of the piece. Sometimes this disrupts the image, which can create chaos. Other times, this enhances the image with clarity.

Like epigenetics, one must follow these fine lines or broad strokes to understand how the larger image, or genome, has come to be. Lupien emphasizes that fostering creative thought can open a world of possibilities for all walks of life. “Bringing these values into your everyday practice as a researcher can serve to nourish your approach to work,” he said.

Experiencing art can also serve as time for our ideas to incubate, perhaps creating a period of unconscious processing for approaching problems in research. Taking from the famous 1929 works of Graham Wallas, The Art of Thought, incubation allows us to process problems in a manner whereby no direct effort is exerted.

We can optimize the way we process pre-existing knowledge by exposing ourselves to creative mediums such as art. This may lead to new approaches in scientific work. Ultimately, generating a scientific discourse with the expression of art can bring forth creative magic that inspires research. 

“In research, there are two things of value — there is knowledge and creativity,” said Lupien.

“You need to have balance. Never shy away from engaging in creative thought. You never know where it will take you.”

As many U of T students were wrapping up classes in March, first-year engineering student Hannah Le and her team won the third Pioneer Tournament — a worldwide competition that rewards participants for developing innovative ideas — for their project that used machine learning to identify and understand human biomarkers that predispose individuals to certain diseases.

Competition participants submit their project online and post weekly progress updates. The project then earns points awarded by contestants, who vote on the updates. After three weeks, the project becomes eligible to win a weekly prize, which is awarded to the team that wins the highest number of points at the end of that week. A project that places as a finalist for three weeks wins the team a larger award.

Le and her team members — Samarth Athreya, 16, and Ayaan Esmail, 14 — earned a top spot on the leaderboard in March and were awarded $7,000 from Pioneer to put toward their project. 

How the team got together

“Samarth, Ayaan and I met each other at an organization called The Knowledge Society in 2017,” wrote Le to The Varsity. The Knowledge Society is a startup incubator that exposes high school students to emerging technologies, such as artificial intelligence (AI), virtual reality, and brain-computer interfaces.

When the three innovators met, Esmail was working on a project that could accurately pinpoint and target cancer cells, while Athreya was working with machine learning models. With Le’s interest in genetics, the three decided to team up and investigate whether there was a way to use metabolic data to predict the onset of a disease.   

“I became incredibly curious on how we can decode the 3 billion letters [of DNA] in every cell of our body to increase human lifespan and healthspan,” wrote Le.

“Inspired by my grandmother who passed away due to cancer, I started asking myself the question: [could] there possibly be a way for us to predict the onset of cancer before it happens, instead of curing it?”

How Le’s team developed a model for predicting the risk of cancer development

At its core, the team’s AI platform uses a patient’s biological information to predict their risk of developing certain forms of cancer.

Metabolites are molecules that play a key role in maintaining cellular function, and some studies have shown that high levels of certain metabolites can signal the progression of lung cancer. But to develop and test their model, the team needed a large amount of metabolic data.

“To overcome such [a] limitation, we had the fortune to reach out to mentors such as the Head of Innovation at JLABS, [a Johnson & Johnson incubator], for further guidance and advice,” wrote Le. “As our team cultivates a stronger database, we would be able to produce more reliable results.”

“As teenagers we were far from experts [in] the field — but we were really hungry to learn,” added Le.

As participants of the Pioneer Tournament, Le and her team received the opportunity to select a board of virtual advisors, who would provide guidance for their project.

“I recalled contacting Josh Tobin at OpenAI to ask him about the use of synthetic data in genomics research,” wrote Le. “[That enabled] us to understand both the strengths and weaknesses of such [an] approach, allowing us to pivot on what models to implement.”

The competition as a learning experience

Le remembers the Pioneer Tournament as an exciting chance to learn about different machine learning models and what made them effective as well as other projects that fellow participants were working on, all while attending courses at U of T.

“First year was an interesting journey of challenging course content, intertwined with unexpected personal growth,” wrote Le. “I learned how to strike a balance between working on personal projects, meeting interesting people, while completing my school work.”

And while Le is intrigued by the intersection of machine learning and genomics, she wrote, “I hope to keep an open mind and continue to be curious about the world around me.”

A recent study published in Nature Genetics sought to determine the effects of hypoxia — low levels of molecular oxygen — on the development of cancer, including how it may speed up cancer growth. Lead author Vinayak Bhandari, a PhD candidate in U of T’s Faculty of Medicine and the Ontario Institute for Cancer Research, examined hypoxia in over 8,000 tumors across 19 tumour types.

Hypoxia can have detrimental health effects, one of which is that it can cause cancer cells to proliferate. 

According to Bhandari, normally, blood vessels in our bodies are well-organized and able to transport nutrients, including oxygen, to all cells. This changes in tumours.

“In tumours, the blood vessels are often very disorganized and have sluggish blood flow,” wrote Bhandari in an email to The Varsity. This leads to low-oxygen tumours. “Around half of all solid tumours end up with low levels of oxygen.”

Hypoxic conditions can accelerate the spread of aggressive cancer cells. In tumours, cancer cells exist with different sets of mutations. Some cancer cells will be susceptible to hypoxic environments due to their specific mutation, and these cells often do not survive. 

“But other cells that have a specific mutation may not be affected by low oxygen,” wrote Bhandari. “So you end up enriching the tumour for cells with that aggressive mutation that can survive an extreme environment and you get a more aggressive cancer.”

Despite the threat that hypoxia poses, it has previously been a challenge to study its effects due to the invasive and difficult process of measuring oxygen levels in tumours. 

To remedy this, Bhandari and his team created an innovative method for examining tumour hypoxia in more detail. 

“We used several mRNA signatures to computationally quantify tumour oxygen levels with existing patient data. We then used this hypoxia information and looked broadly at lots of different genomic features of tumours and found some really interesting links in several cancers,” wrote Bhandari. “We then dug deeper into prostate cancer where we have really good long term data for how patients respond to treatments and we looked further into interactions between hypoxia, changes in the DNA and also how tumours change over time.”

Dr. Paul Boutros — former Associate Professor at U of T’s Department of Medical Biophysics, now at the University of California, Los Angeles, and the supervisor for this study — added that hypoxia and its relevance to cancer growth is still not well understood, but that this research is a significant step. 

“I think other researchers are going to be able to take advantage of these data to explore a lot of new angles,” wrote Boutros. 

Boutros believes that other researchers will begin to look at genomics associated with hypoxic cancer cells, and begin to look more into genomic data in a new light. Boutros also adds that this research highlights how hypoxic environments arise due to different factors aside from genetic mutations, including cell morphology and evolutionary properties. 

Bhandari emphasized the multidisciplinary nature of the team involved in the research, and how it was an asset. 

“We were only able to do this because we had biologists, chemists, data scientists, statisticians, engineers, pathologists and radiation oncologists come together to work on this problem in asymmetric fashion. Everyone contributed in important ways over many years and I think this is the best way forward for answering difficult questions.”

YAP and TAZ are proteins that have long been recognized for their role in regulating transcription — a process in which the information in DNA is copied into RNA — and are particularly relevant in cancer development.

A recent study in Nature Communications led by Mandeep K. Gill in U of T’s Department of Biochemistry identified NUAK2 as a gene that could control YAP/TAZ activity.

In normally functioning cells, YAP and TAZ are responsible for forming and regenerating tissues. In tumours, however, these proteins are able to initiate and metastasize, or spread, cancer cells to other parts of the body, as well as initiate the tumours.

“The relatively recent discovery (roughly 10 years) of the so called  ‘Hippo pathway’ which normally acts to limit excess cell growth and the demonstration that it is turned off in most cancers has provided a new target for the development of therapeutics,” explained Liliana Attisano, a principal investigator of the study also from the Department of Biochemistry, in an email to The Varsity.

The Hippo pathway is a process that controls tissue and organ development in mammals, especially in their size, by regulating cell growth and death, and controls the transcriptional activity of YAP and TAZ proteins.

The pathway can be activated by various factors, after which it engages its core cassette — a subunit made of enzymes known as kinases, which are involved in the movement of phosphate groups, or phosphorylation.

When a cascade of phosphorylation — the addition of a phosphate group — occurs in the cassette, YAP and TAZ are marked with phosphate groups and are targeted for degradation.

When the Hippo pathway is inactive, however, YAP and TAZ accumulate in the nucleus and latch on to the DNA-binding proteins in there, which can lead to cancer cell proliferation. 

Attisano and her team discovered NUAK2 was found to encode a protein that results in even more YAP and TAZ getting into the cell’s nucleus to further promote abnormal cell growth.

The researchers started by conducting studies in breast cancer cells and were able to identify  the kinase NUAK2 as a positive regulator of YAP and TAZ activity.

According to the study, “NUAK2 functions in a kinase-dependent manner to promote nuclear YAP/TAZ localization and activity” and promotes YAP and TAZ activity in a positive feedback loop.

A decrease in NUAK2 is therefore found to reduce transcriptional activity and the quantity of YAP and TAZ in the nucleus. As well, kinase-deficient NUAK2 was found to restore YAP and TAZ localization in the nucleus, which deemed NUAK2 an activator of YAP and TAZ activity.

“We found a way to restore the activity of the pathway (by removing or blocking NUAK2 activity),” wrote Attisano.

A lack of NAUK2 in cells showed a reduced cell growth and robust tumour growth in mice.

Tests were conducted on bladder cancer cells to determine the implications for human tumour progression. Larger increases of NUAK2 were found in high-grade samples that came from patients who had experienced a relapse.

These findings could be applied to cancer treatments as blocking the expression of or inhibiting NUAK2, YAP, and TAZ appears to restore Hippo pathway activity and cell growth, thus limiting tumour progression.

“There is still a long road ahead,” wrote Attisano. “But the next step would be [to] develop specific and potent compounds that can be tested in mouse and human organoid models with the long-term goal of… identifying a drug that can be used in patients.”

A biotech startup co-founded by Sachdev Sidhu, a professor in U of T’s Department of Molecular Genetics, has drawn in $62 million USD following a second round of funding, bringing its total investments to $72 million USD.

Pionyr Immunotherapeutics, which is now planning to take its anti-cancer therapy to clinical trials, initially began as a research collaboration between Sidhu and Max Krummel, a professor at the University of California, San Francisco School of Medicine. Founded in 2015, the California-based startup combined Sidhu’s expertise in antibody phage-display technology with Krummel’s immune system biology research.

This project is a collaborative effort with Toronto Recombinant Antibody Centre (TRAC), which was founded by Sidhu and Dr. Jason Moffat, who is also a Molecular Genetics professor at U of T. Housed in the Donnelly Centre for Cellular and Biomolecular Research, TRAC researchers are working to harness the therapeutic potential of synthetic antibodies.

Synthetic antibodies can be engineered to target a variety of molecules implicated in disease and they are key for drug development. Pionyr’s anti-cancer therapy, known as Myeloid Tuning, uses the high specificity afforded by synthetic antibodies to bolster the immune system’s defence against cancer by manipulating a tumour’s microenvironment.

The immune system uses T cells to detect foreign molecules to evoke a defensive response. Because tumours are created from existing cells in the body, they evade recognition by T cells, dampen the immune response, and proliferate uncontrollably. The key is to restore the body’s immune capacity to fight cancer — this is the premise of immunotherapy in oncology, better known as immuno-oncology.

“So the idea there is simple: you want to turn on a T cell, you simply find proteins that are inhibiting that T cell,” said Sidhu.

Myeloid Tuning achieves this by “alter the tumour microenvironment to favour immune-activating cells over immune-suppressing cells” and enhances anti-tumour defenses. “T cells are activated not by targeting them but by eliminating the inhibitory cell population,” said Sidhu.

Pionyr’s technology could also complement existing anti-tumour therapies like T cell checkpoint inhibitors. Checkpoints are regulators that mediate communication between T cells and the immune system. They are responsible for fine-tuning the body’s immunity and downregulating it when it detects native cells, which would otherwise lead to an autoimmune response. By incorporating checkpoint inhibitors, therapies can be developed to block a tumour’s ability to evade T cell detection.

Ipilimumab, commercially known as Yervoy, set the precedent by becoming the first United States Food and Drug Administration-approved therapeutic antibody against skin cancers and for ushering in a new wave of immuno-oncology. The drug, co-invented by Krummel, inhibits cytotoxic T-lymphocyte-associated protein-4, one of many checkpoints found on T cells. Similarly, pembrolizumab, or Keytruda, inhibits the checkpoint called programmed cell death protein 1 (PD-1).

“Anti-PD-1 binds the T cell and… activates it that way, and then we add another antibody that eliminates inhibitory myeloid cells, so you get double [the effect],” said Sidhu.

Sidhu says there is a critical question in field: does the rest of the tumour simply not have T cells that can attack them or are there additional yet unidentified breaks? These possibilities are not mutually exclusive and are already being investigated. According to Sidhu, the future of immuno-oncology is already here.

Myeloid Tuning is a very promising method, but it is not the only immuno-oncology treatment in the works. Currently, therapeutic agents being researched involve other immune cells like macrophages and natural killer cells that can be exploited for anti-tumour therapies.

“[There is] very little that is not being explored as far as immune cell activation,” said Sidhu. “It’s exciting in that, while only a subset of cancers responds to immunotherapy, the ones that do respond often respond tremendously.”