By Patrick Ammerman

Oftentimes the most important scientific work is accomplished via serendipity; by following up on an unexpected finding and uncovering an entirely new area of research.

Susan Volk, assistant professor of small animal surgery at the University of Pennsylvania’s School of Veterinary Medicine, has done just that in her career. Following a thread that connected her original specialty of wound healing with cancer biology, she has gained new insights into both fields. At its core, her research strives to improve care for her surgical patients by helping develop better treatments for animals, with potential applications for humans down the road.

Volk received both her veterinary and doctoral degrees from Penn, through Penn Vet’s combined V.M.D.-Ph.D. program. She began her program determined to be a surgeon, but, during the Ph.D. portion of the program, realized just how important basic science discoveries were to her patients. She took an interest in wound healing, because of its direct impact on how her surgical patients recover after a procedure. It was a Penn Vet professor and mentor, David Nunamaker, who inspired her approach.

“He was a pioneer in clinical veterinary orthopedics and yet his research focused on how to prevent career-ending fractures in racehorses from developing in the first place,” said Volk. “A lot of what we do in my lab now is to allow us to go beyond what we can accomplish in the operating room, first, by sparing our patients from surgery by preventing disease or discovering less invasive and more effective approaches, and second by improving upon their clinical outcomes when surgery is warranted through the development of innovative complementary treatments.” 

Similar to human patients, companion animals that sustain traumatic injuries can experience suboptimal healing at both ends of the spectrum, either poor healing or healing with excessive scar formation. The search for interventions that heal wounds faster and completely but with less scarring remains an area of intense research. Such therapies are particularly vital in elderly individuals.

“Many people develop chronic wounds associated with age,” said Volk. “We have an aging population that has increased incidence of comorbidities such as diabetes and obesity, resulting in increasing wound healing complications.”

In 2009, Volk’s research in this area took her down a surprising path. She was in the midst of a wound-healing study, in which she was using mouse models to investigate how tissue repair differed in animals lacking certain genes. In one strain of aging mice, which were deficient in a protein called type III collagen, Volk noticed that the incidence of tumors was higher than in their normal littermates. She hypothesized that this type of collagen, a protein known to promote optimal healing responses throughout the body, may also function to suppress tumor formation and progression.

Once she began looking more deeply into the role of this protein in directing cell behaviors within tissues, she soon realized she may have stumbled upon an important regulator of mammary gland tumors. Although there was a strong foundation of work showing that collagens play an important regulatory role in cancer, this was the start of a series of investigations to better understand the role of type III collagen in both wound healing and in breast cancer biology.

“For me it was very interesting because, for a long time, tumors have been described as wounds that don’t heal,” says Volk.  “After our initial discovery that type III collagen may have tumor-suppressive properties, we really applied what we had learned in our wound-healing research to cancer biology.”

Since then, Volk and colleagues have found that type III collagen helps prevent the spread of mammary gland tumors. It appears to play a role in regulating cancer cell behavior by its direct interaction with cancer cells, by controlling the activities of non-cancerous cells within the tumor and by influencing the structural and chemical  environment outside cells to prevent metastasis, or the spread of cancer to other locations in the body. The presence of type III collagen also may limit local recurrence of a tumor after it is removed through a combination of its tumor-suppressing and wound healing-promoting properties.

Specifically, Volk has discovered that type III collagen can regulate the activation of myofibroblasts, a type of cell that normally participates in healing skin after injury. Usually these cells disappear in the later stages of repair, but in some cases they persist and promote excessive scar formation. Research from other groups has also suggested that myofibroblasts can also play a role in organ fibrosis and cancer progression. Working with colleagues in veterinary and human medicine, biochemistry, immunology and tissue engineering, Volk hopes to understand how properly functioning type III collagen inhibits formation of these myofibroblasts, findings that may be applied to patients with either healing disorders or cancer, whether they are companion animals or humans.

Volk maintains the perspective of a clinician in her surgical practice, which regularly brings her in contact with patients affected by cancer. In collaboration with Karin Sorenmo, professor of oncology at Penn Vet, and Ellen Puré, chair of Penn Vet’s Department of Biomedical Sciences, Volk is applying her findings on the role of the tumor microenvironment in breast cancer to dogs through the work of the Penn Vet Shelter Canine Mammary Tumor Program.

Mammary tumors are the leading cause of cancer in unspayed female dogs.  Although surgery remains the mainstay for treatment, approximately half of all mammary tumors in dogs are malignant and thus potentially require additional treatments to address distant metastasis.

The program treats dogs that are considered low, medium and high risk for their tumors metastasizing. But a goal is to learn how to better evaluate risk of metastasis, to prevent both over- and under- treatment of patients. Volk is also hoping that this population will help to identify signs that may predict recurrence of the tumor after surgery and to find novel ways of treating those recurrences.

Volk hopes that her basic research and surgical work can together make cancer treatment better informed and more effective. Innovations in treatments for dogs may be applicable to human patients down the line, such as interrupting the spread of cancerous cells. Her work is a part of the new Cancer Center initiative at Penn Vet, launching in fall 2017 to combine various approaches to cancer research and foster novel therapies for patients.

“Metastasis is something that we can’t necessarily control with our surgical approach,” she says, “so this research asks, how can we improve our chance of a successful outcome?”

One answer may be the use of the biomaterials used in reconstructing tissues after surgical removal of tumors. Although these biomaterials may help surgeons improve cosmetic outcomes for their patients, Volk is investigating how applying her basic science discoveries to the design of these materials could also improve post-surgery healing and reduce cancer recurrence in patients as well.