A University of Alberta research team is shedding much-needed light on cancer cachexia, a severe muscle-wasting syndrome linked to up to a third of cancer deaths.
The research published in Nature reveals the complex biological processes behind cachexia in patients with cancer, providing potential targets for future treatments. The researchers also identify two main molecular subtypes of muscle tissue in cancer patients, with one subtype more likely to be associated with signs of cachexia.
Although much effort has been spent on mapping genes found within cancer tumours, this is the first time the genome of muscle tissue affected by cancer has been mapped.
"It takes 10 years for an aging person to lose two to four per cent of their muscle," says principal investigator Sambasivarao Damaraju, professor emeritus in the Faculty of Medicine & Dentistry and adjunct professor in the Faculty of Agricultural, Life & Environmental Sciences. "Cancer patients can lose up to 20 per cent of their muscle within six months, and it's a very hard thing to reverse."
This severe muscle loss leads to compromised quality of life, caregiver burden and overall mortality for patients, explains Damaraju.
"Until we fully understand the molecular architecture of cancer cachexia and its complexity, we cannot attempt to develop therapeutic modalities to halt or even reverse it."
Much of the understanding of cancer cachexia thus far has come from animal experiments that do not fully mimic the trajectory of the disease in humans. Damaraju predicts the new findings will shape cachexia research for the next decade.
A new direction for research
Cancer cachexia affects up to 75 per cent of those with advanced cancer, according to Damaraju. There is no targeted drug treatment available. The syndrome is diagnosed by tracking weight loss, compromised muscle function, and CT scans of diminishing skeletal muscle mass, but these criteria are not sufficient to understand underlying molecular or physiological changes.
The team examined rectus abdominis muscle biopsies from 84 patients with pancreatic and colorectal cancer. They used state-of-the-art methods of molecular profiling to map the complete RNA transcribed within the muscle cells. They then analyzed the results with artificial intelligence to look for patterns to explain the variations in muscle loss.
They identified two distinct molecular subtypes, with Subtype 1 associated with increased clinical manifestations of cachexia such as severe weight loss, low muscle mass, atrophy of muscle fibres and reduced survival compared with patients in Subtype 2. Subtype 1 tissue was associated with problems ranging from dysregulated protein production and neuron malfunction to immune-related inflammation and metabolic abnormalities.
Previous studies looked at only limited sample sizes of human muscle tissue and focused on protein-coding RNAs. This paper also examined other RNAs, including non-coding RNAs with regulatory functions. The authors document that "crosstalk" within the various RNA classes explains the hierarchy of gene regulation in muscle.
"In a healthy person, there is a constant turnover of the muscle that is broken down then rebuilt, then broken down and rebuilt again," Damaraju explains. "In cancer cachexia, a lot of catabolism or muscle breakdown is happening, but the muscle synthesis or the anabolic processes are never catching up. All of the muscles in the body are affected."
A better target for new drugs
Damaraju says the few new drugs in development to treat cachexia target the functions of a single protein. This new research identifies "master regulators" among the non-coding RNAs, which could serve as more effective targets with an impact on several downstream signalling molecules and proteins at once.
He notes that a new class of drugs known as antisense oligonucleotides is being used to target RNA to treat forms of muscular dystrophy, and this approach might be useful in cachexia as well.
Damaraju hopes the work may also stimulate research to identify the molecular mechanisms behind cachexia in other diseases such as COPD, heart failure and kidney disease.
Damaraju credits a multidisciplinary team, mostly based in Alberta, with expertise in molecular biology, genomics, bioinformatics, and surgical oncology. The doctoral student who was first author on the paper, Bhumi Bhatt, had to develop expertise in a multitude of tools and techniques, Damaraju notes, and the Nature paper includes her entire thesis.
"Dr. Bhatt had to understand muscle biology, molecular biology, clinical classification of the muscle using CT, statistics and machine learning to meet the study objectives," Damaraju says. "Not very many students will have the distinction of a Nature paper when they graduate. Her future is very promising."
Bhatt plans to go on to medical school next. She was supported through her studies by various scholarships and awards including the Bell McLeod Professional Development and Educational Fund Travel award, the Graduate Research Assistantship and the University of Alberta Doctoral Recruitment Scholarship.
The work was funded by the Canadian Institutes of Health Research. The research team also included oncology professor Vickie Baracos, who is a member of the Order of Canada, professor of agricultural, food and nutritional science Vera Mazurak, adjunct clinical professor of oncology Sunita Ghosh, University of Calgary cancer surgeon Oliver Bathe, and exchange student Aurélien Brun of Université Clermont Auvergne in France. Baracos and Ghosh are members of the Women and Children's Health Research Institute. Damaraju, Baracos and Mazarek are members of the Cancer Research Institute of Northern Alberta. Part of the work was conducted in the U of A's Cell Imaging Core.
