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a. Type III Collagen plays an important role in repair and healing throughout the body

The extracellular matrix protein type III collagen (green) is expressed by differentiating cells during healing of many tissues, including bone fracture repair.

The Volk lab has defined a role for Col3 in limiting fibrosis through its effects on scar-forming myofibroblasts. In addition, Col3 also directly regulates regenerative activities of other cell types in the healing process.

Human Keratinocytes Migrating in Culture

b. Accelerating Wound Closure

Epithelialization is a defining feature of a healed wound. Improving the ability of keratinocytes to close a wound following trauma will improve the lives of people and animals suffering from chronic wounds.

By studying cues that direct keratinocyte migration (human keratinocytes in culture seen here), our laboratory hopes to improve healing of problematic wounds.

c. Controlling Scar formation/Fibrosis/Desmoplasia

Type III collagen (Col3) is the second most abundant collagen in the body. A series of studies from our laboratory have identified a key role for Col3 in limiting activation and persistence of myofibroblasts, the cellular effectors of scar formation, fibrosis and desmoplasia in tissue repair and tumor microenvironments. Here, Col3-deficient fibroblasts show incorporation of the myofibroblast marker alpha-smooth muscle actin in stress fibers. Applying this knowledge, we hope to control myofibroblast activity and fate to restrict pathologic responses to cancer and following injury.

d. Matrix-Degrading Enzyme Activity Facilitates Cancer Metastasis

Matrix-degrading enzyme activity (green) clears a pathway for invading breast cancer cells (red) at the tumor-stromal border.

Understanding how this process is controlled and determining safe, effective strategies to limit its occurrence in tumor may prevent aggressive cancer behaviors, such as local invasion and distant metastasis.

e. Collagen Matrix

There is a dynamic interaction between cells and their surrounding extracellular matrix. Collagen directs cancer cell activities and fate but these cells in turn modify the matrix by altering its structure, organization and density. Breast cancer cells (purple) reorganize the collagen matrix (blue) between two cell aggregates and preferentially migrate across this aligned matrix “bridge”.

f. A dynamic relationship between cells and their microenvironment

Dynamic reciprosity defines the ongoing, bidirectional interactions between cells and their surrounding microenvironment (including soluble factors and the extracellular matrix) that occurs in tissues undergoing physiologic or pathologic processes. Here, a human breast cancer cell can be seen interacting with surrounding collagen in culture. Our laboratory is interested in defining how individual collagen types control cancer cell behaviors and also how these cells in turn modify their surrounding matrix to learn how to control invasion and metastatic spread of tumor cells.

g. Collagen in the Canine Mammary Tumor Microenvironment

Collagen signatures in biopsy samples of women with breast cancer have been shown to predict clinical outcome. Label-free two-photon-second harmonic generation imaging reveals dense collagen (blue) within a malignant mammary tumor of a dog. Ongoing studies in our lab have identified specific collagen signatures that are associated with aggressive biologic behavior in canine patients with malignant mammary cancer. Additional studies are aimed at the development of safer, more effective therapies for dogs and cats with aggressive cancer based upon our basic research findings. We anticipate these studies may also help people with cancer.

h. From Labrador to laboratory and back!

Adult stem cells taken from a dog can be differentiated into bone forming cells in culture. The Volk laboratory seeks to understand the complexity of how these cells improve tissue repair and function to optimize their regenerative capacity. Dr. Volk and Dr. Kimberly Agnello have completed enrollment for their first clinical trial to compare the efficacy of adult stem cells isolated from different tissues to improve clinical outcomes in young dogs with surgically-treated bilateral fragmented medial coronoid processes.