Major projects in the laboratory include:
Defining a role for type III Collagen (Col3) in regenerative and tumor microenvironments
Our publications have characterized a key role for Col3 in directing cellular activities and fate in regenerative and tumor microenvironments.
Although Col3 has been widely speculated to play a role in wound healing due to its temporospatial pattern of expression following injury, our studies were the first to reveal a role for Col3 in 1) regulating reepithelialization and scar formation during cutaneous wound healing and 2) modulating bone formation during development and fracture repair. These studies have important implications for the development of novel strategies to target major medical issues such as chronic non-healing wounds, disorders of excessive scar formation, impaired bone healing and osteoporosis. Our study showing that Col3-deficiency promotes scar deposition through the promotion of myofibroblast density and persistence following injury has led to a paradigm shift in the understanding of how individual collagens can suppress scar formation/fibrosis rather than simply contributing to the process. Ongoing studies seek to define mechanisms by which Col3 regulates cell activities and fate and apply this knowledge to the development of novel biomaterials for tissue engineering strategies.
As tumors have been referred to as “wounds that do not heal”, our recent publication identifying a role for Col3 in suppressing breast cancer growth and metastasis by its ability to direct stromal organization complements our wound healing studies. Current studies will determine mechanisms by which Col3 regulates the switch between a tumor-restrictive and tumor-permissive stroma and address the hypothesis that Col3-based regenerative strategies can effectively limit recurrence of certain cancers.
Regenerative therapies for cutaneous wound healing
The extremes in response to cutaneous injury, both non-healing chronic wounds and pathologic scar formation, are a significant cause of morbidity and health care expenditures. Together with collaborators, our laboratory has shown regenerative medical strategies (cell-based therapies, electrical stimulation and biomaterials) improve quality of cutaneous wound healing, and determined mechanisms by which they promote optimal repair, using small and large animal models as well as in human subjects.
Cellular-based therapies to improve tissue repair in canine models
Our laboratory has a long-standing interest in adult cell-based therapies, with a goal to develop and then optimize novel treatments to improve healing of companion animals. Studies in my laboratory have focused on advancing a thorough, systematic understanding of the basic biology of canine MSCs to inform the design of future stem cell clinical trials in the dog and their use for translational studies. As spontaneous large animal models play a key role in defining efficacy of regenerative medical therapies, these early studies have provided critical data for model development. Our current clinical trial in client-owned dogs with elbow dysplasia will compare efficacy of post-operative cell-based therapies (bone marrow vs adipose-derived) in improving clinical outcomes.
Stromal targets in cancer of companion animals
Studies from a large number of laboratories, including our own, have revealed a critical role for the tumor stroma in controlling cancer behavior. As aggressive stromal signatures predict metastasis and survival in both murine breast cancer models and human patients, we predict these signatures may provide similar prognostic information in dogs and cats with mammary gland tumors. Mammary gland tumors, the most common malignancies in intact female dogs, represent a significant canine health problem. Two major obstacles limit our care of dogs with mammary carcinoma: 1) accurate identification of dogs at high-risk of local recurrence and/or metastasis and 2) effective therapies for at risk individuals.
In collaboration with Dr. Karin Sorenmo, Director of the Penn Vet Shelter Canine Mammary Tumor Program, and Dr. Ellen Pure, Chair of the Department of Biomedical Sciences at the School of Veterinary Medicine and an internationally-recognized expert in the field of the tumor microenvironment, our on going studies aim to:
- Identify stromal signatures that predict recurrence/clinical outcomes in dogs with mammary gland tumors to avoid over-treatment of low-risk patients as well as under-treatment of those that require early, aggressive intervention
- Determine mechanisms driving formation of a tumor permissive stroma
- Develop safer, more effective therapies for patients with mammary tumors
Although our initial studies have focused on canine mammary tumors, we have also begun applying our findings to cancers in cats as well. As spontaneously occurring canine and feline mammary carcinomas share many similarities with human breast cancer, our findings may have direct application to human breast cancer research, thus helping both dogs and women with breast cancer.