Cancer without end? Discovery yields fresh insights


August 1, 2019

If there is any consolation to be found in cancer, it may be that the devastating disease dies with the individual carrying it. Or so it had long been assumed. Recent research, however, has uncovered some forms of cancer that are transmissible, jumping from one host to another. Indeed, one such contagious cancer, known as canine transmissible venereal tumor (CTVT), has managed to persist in dogs for thousands of years.

In a new commentary appearing in the Aug. 2 issue of the journal Science, Arizona State University's Carlo Maley and University of Southern California's Darryl Shibata describe the dynamics of this sexually transmitted disease, which arose in a single ancient animal, living as much as eight-and-a-half millennia ago. CTVT first emerged in a dog that lived 4,000-8,500 years ago. All CTVT tumors carry the DNA belonging to this “founder dog." By counting and analyzing the mutations acquired by CTVT tumors around the world, researchers can piece together how and when CTVT emerged and spread. Artist’s impression of the “founder dog” that first gave rise to CTVT. This dog’s phenotypic traits were interpreted from the genetic variation found in the DNA of the cancer that it spawned. Image credit: Emma Werner Download Full Image

Intriguingly, the exploration of long-term, multigenerational cancer evolution in CTVT may shed new light on how human cancers evolve during the typical course of the disease and may inspire new approaches to treating cancer, which remains the second leading cause of death worldwide.

“Cancers evolve, and our strategies for managing cancer need to take that into account,” Maley said. In the future, we hope to maintain long-term control over these evolving tumors. CTVT is fascinating because it shows us how cancers might evolve over the long term.”

Maley is a researcher in the Biodesign Center for Biocomputing, Security and Society, the Center for Immunotherapy, Vaccines and Virotherapy and the Center for Mechanisms of Evolution at Arizona State University, as well as ASU’s School of Life Sciences. He is the director of the newly established Arizona Cancer and Evolution Center (ACE). Shibata is a professor in the Department of Pathology at USC and the co-director of the ACE Center.

Ominous signs emerge

Examples of contagious cancers in humans exist, but they remain exceedingly rare and have never spread beyond a second host. Other animals are less fortunate and may fall prey to a range of transmissible cancers, which vary in the severity of their impact.

In 1996, a mysterious illness began sweeping through animal populations in the central highlands of Tasmania. The island’s Tasmanian devils were dying from a gruesome facial tumor. At first, a virus was the suspected culprit in the rapidly spreading epidemic. But when the DNA fingerprints of afflicted devils were examined, researchers made a remarkable discovery. The tumor cells were genetically distinct from the devil’s own healthy cells, yet they matched tumor cells taken from other Tasmanian devils with the facial tumor disease. It was as though the tumor cells had been cloned and transplanted into each stricken animal. The disease was positively identified as an aggressively lethal, transmissible cancer.

The current commentary concerns CTVT, which causes grotesque, oozing tumors that afflict the genital area in dogs. When researchers sequenced cells from these tumors, the results mirrored those observed in the Tasmanian devils. All of the cancer cells shared a suite of genetic variants that did not appear in the dogs’ healthy cells. This led to a startling conclusion: CTVT is not simply a disease that occasionally develops in dogs. It arose only once, in a single dog and has been transmitted through the ages from one animal to the next ever since.

When two dogs with CTVT were examined, one in Brazil and another in Australia, each belonging to a different breed, their tumor cells shared nearly 2 million mutations that were not found in normal canine DNA. While the CTVT genome diverged considerably from the original dog genome, it remained remarkably stable over time.

A contagious form of cancer known as canine transmissible venereal tumor (CTVT) has been affecting dogs for thousands of years. The evolution of this disease could hold vital insights for the study and treatment of human cancers.

Dog years

Unlike the pitiless cancer devastating the Tasmanian devils, CTVT is rarely lethal. Instead, it typically persists for a matter of months before being cleared by the dog’s immune system. (See drawing based on genetic sequencing of what the first dog carrying CTVT may have looked like.)

Recent investigations of CTVT, carried out by Adrien Baez-Ortega and colleagues, advance the unusual story of this disease. Their findings appear in the current issue of Science and are the focus of Maley and Shibata’s commentary. 

Baez-Ortega, a researcher at the University of Cambridge, sequenced tumors from 546 dogs around the world. The results showed the great antiquity of CTVT, which has been transmitted by dogs for 4,000 to 8,500 years. For evolutionary biologists like Maley and Shibata, the findings are revelatory, in part because CTVT appears to have stopped evolving long before it spread around the world.

New directions

The study of cells derived from transmissible cancers like CTVT provides valuable clues for biologists interested in the development of human cancers. Examining somatic cell evolution around the world and over significant spans of time helps researchers understand the subtle dynamics of the evolutionary processes involved in cancer. (In contrast, observing the life and death of cells over time in an individual patient is very difficult.)

Perhaps the most critical observation resulting from the genome sequencing of CTVT is that cancer is not an inevitably progressive disease. Rather, tumors may reach an optimal state that can stabilize over time, exhibiting little or no additional gains in biological fitness — the ability to survive and reproduce.

Typically, tumors persevere and wreak havoc by generating numerous mutations. While most of these have no effect on cancer cell survival, or are even harmful, a few convey an adaptive advantage to cells, increasing their survivability. These are known as driver mutations and as the name implies, they are responsible for a successful cancer’s relentless expansion. Driver mutations generate the cells that are able to resist cancer treatment.

It appears that CTVT has been evolving neutrally after its inception, accumulating mutations that do not affect fitness. The successful development of CTVT in dogs therefore seems to require only a few minor adjustments to the genome. The lack of ongoing natural selection in CTVT also suggests that the disease has not had a significant impact on dog survival and reproduction.

The stability of CTVT over time offers hope that certain slow-growing human cancers resistant to conventional therapy, for example prostate cancer, could be tamed and controlled. This might be achieved through so-called adaptive therapies, which seek to limit tumor growth as opposed to aggressive treatments aimed at total eradication, which invariably select for resistant and often lethal cell variants. A pilot clinical trial to test this approach in metastatic breast cancer will soon start at Mayo Clinic’s Arizona campus, in collaboration with ASU.                                             

It seems likely that ongoing explorations of cell evolution in CTVT will provide further insights into complex cell trajectories and genetic transformations in a range of human cancers and inspire innovative methods of addressing the disease.

“Most cancers can only evolve for a few decades before they die with their host,” Maley said. “CTVT is an incredible natural experiment, which showed us that it doesn’t take much for a cancer to reach an optimal state. It is amazing that it did not discover additional adaptations over thousands of years, even as it infected all different breeds of dogs in all different environments around the world.”

Richard Harth

Science writer, Biodesign Institute at ASU

480-727-0378

 
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ASU alumna makes big ripples in Lake Havasu City

August 2, 2019

Biology major Briana Morgan is municipality's water conservation specialist

There aren’t any great white sharks in the Colorado River, but a picture of them captivated Briana Morgan and propelled her into a career of working on water conservation in Lake Havasu City.

Her visiting great uncle, an underwater photographer, showed her pictures of the predator he had snapped. She was 7 at the time.

“It was definitely a pivotal moment for me, and I was instantly captivated,” said Morgan, who is Lake Havasu City’s current water conservation specialist. “That captivation instantly took over me because every waking moment I watched documentaries, bought books, did research and was intrigued by underwater life and everything that had to do with water.”

Morgan, who graduated from Arizona State University at Lake Havasu in 2016 with a bachelor’s degree in biology and environmental science, said her passion for the environment and conservation was not only stoked by her uncle, but fueled by personal circumstances.

The Lake Havasu City native suffered from a growth deformity called leg length discrepancy in her youth. Morgan’s right leg was 3.5 inches shorter than her left, which didn’t allow her to participate in many physical or outdoor activities with her friends. Her parents stressed education as an avenue to a better life.

“We shared with Briana that she needed to concentrate on her studies because she was going to need a good job with insurance in case she had more medical issues,” said her mother, Cherith Morgan. “Briana also had a good attitude because if she faced a challenge, her mindset was always, ‘I’ll conquer it.’”

A series of surgeries corrected Morgan’s leg when she was a teen, but when she was about to graduate high school, a new crisis emerged: Morgan’s father was diagnosed with stage 4 colon cancer.

“He was very strong, very stubborn but also encouraging,” Morgan said. “He fought to the very last day and one of the last things he told me was, ‘I’m not going anywhere. I will be here to see you do all of these wonderful things.’”

Sadly, that was not the case. Bill Morgan died a week before his 52nd birthday on July 13, 2012. A month later, Morgan started her freshman year at ASU.

“His death was definitely traumatic and emotional, but as far as college was concerned, it was a breath of fresh air and I needed it,” Morgan said. “I went into college highly motivated.”

Morgan blazed through her freshman year but was severely slowed down when she was a sophomore. That’s when she suffered a grand mal seizure a few days before the first anniversary of her dad’s death. Most seizures last between three and five minutes. Morgan said hers lasted between 20 and 30 minutes.

The damage was hefty. Morgan was placed on medication that slowed her down and didn’t allow her to drive for six months. She also lost a good chunk of memory and was forced to retake a calculus class.

“There were a lot of street names and routes I forgot, and to this day I still can’t remember a lot of my high school years,” Morgan said. “I don’t remember my father’s funeral at all.”

The seizure and ensuing epilepsy diagnosis not only forced Morgan to take a good look at her life, but also her future. She was studying to become a field biologist but figured she might become a liability because of her condition. So she switched her focus from biology to water conservation in her sophomore year.

One of her thesis/capstone projects focused on the Colorado River, its importance, issues it faces regarding shortages, impacts on stakeholders and a call to action for conservation.

The timing was fortuitous.

Months before Morgan graduated, Lake Havasu City’s water conservation specialist position was up for grabs. According to Doyle Wilson, water resources coordinator at Lake Havasu City and Morgan’s boss, she gave a great interview. Wilson interviewed close 50 candidates before hiring Morgan.

“She’s grown into the position, and her job has grown as well,” Wilson said. “Briana is very dependable and works well with others.”

One example of Morgan's work is an April 2017 landscaping project with Mohave State BankNow State Bank of Arizona in Lake Havasu in which she suspected there were leaks and came up with a redesign that was not only more aesthetically pleasing, but saved the city thousands of gallons a year in water consumption.

Lisa Van Ella, the bank’s vice president of community development, reached out to Morgan when she noticed the bank’s water bills were extremely high. Prior to the landscaping project their irrigation usage was averaged almost 30,000 gallons a month, or a couple of average-size swimming pools worth of water according to Van Ella.

“I kept wondering why are our water bills so high,” Van Ella said. “And our landscaping looked terrible. We definitely had some issues, which is why I called Briana.”

Morgan quickly swung into action with a mission to beautify the landscaping while conserving water. She also enlisted ASU’s Environmental Community Outreach club, a club she belonged to while attending the university. They mapped out the logistics of the transformation of the bank as part of their classwork.

They determined the bank’s irrigation system not only had major leaks, but needed a new design to include water-friendly plants and vegetation, and bioswales and other landscape elements to absorb surface runoff. They discovered the bank experienced 56,000 gallons of water running off its hard surfaces from an average annual rainfall of 4.24 inches.

The yearlong project ended on Earth Day 2017 with students and bank employees pitching in to install a drought-tolerant plant selection and green infrastructure. ASU students also made sure that whatever was taken away from the property was repurposed for another use.

Not only did the bank look better, but it was operating more efficiently. Its water usage also decreased by 76%-86% every month.

“We saw immediate results regarding our water bill,” Van Ella said. “The amount of money we invested into the project came back to us over time. We have Briana to thank for this.”

The city recognized the bank with the “Lake Havasu City Water Conservation Recognition Award” in 2018. That was the same year the Havasu News Herald selected Morgan as the youngest awardee for Havasu’s 30 under 40 Up-and-Coming Leaders. The award recognizes the city’s best and brightest young leaders.

“Briana is the right person at the right time for Lake Havasu water conservation,” said Raymond Van der Riet, director of ASU at Lake Havasu. “As an environmental science student, she always demonstrated a knack for applied solutions. Briana’s keen analytical approach to problem-solving is much needed in Lake Havasu City, where the economy is directly impacted by the ebb and flow of the Colorado River. There is no doubt the city is in good hands.”

In addition to community education, grant writing, water audits and pressure checks on homes and businesses, Morgan juggles other assignments: She facilitated Lake Havasu City’s rebate program that helped residents obtain water-saving appliances at discounted prices; is heading up a rainwater/grey water harvesting project for two of the city’s municipal facilities; established the city’s Recommended Landscaping Plant List and is in the process of converting it to a database that will soon be available on the city’s website. She was also responsible for helping Lake Havasu City win third place for 2018 in the Wyland National Mayor’s Challenge for Water Conservation and fifth place in 2019.

She also assisted New Horizons, a nonprofit that assists persons with disabilities, with a community garden project on a vacant city lot. Morgan helped in the planning and design phase, ensuring the landscaping was desert-friendly and graded to prevent flooding in the walkway areas during storm events.

The community garden currently leases planting beds to residents who grow vegetables and share them with the community. It hopes to open a farmers market in the fall and hold events such as weddings, meetings and wine tastings.

One could argue that Morgan is finding her own success through perseverance. However, she doesn’t forget that she had to fight every step of the way.

“I get that comment a lot. ‘Wow, you’re so strong. I don’t know if I could do that,’” Morgan said. “The reality is people are built to fight, and they’re meant to fight. It’s just whether or not they’re put into that situation. I think everybody has a fighter inside of them; it’s just a matter of bringing it out.”

Top photo: ASU at Lake Havasu City graduate Briana Morgan is the municipality's water conservation specialist in the western Arizona community. Morgan poses at the city's water treatment plant, where she gives tours. Photo by Charlie Leight/ASU Now

Reporter , ASU Now

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