Philadelphia University + Thomas Jefferson University

Bussard, Karen

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Karen M. Bussard, MS, PhD

Karen M. Bussard, MS, PhD

Contact Dr. Bussard

233 South 10th Street
BLSB 624
Philadelphia, PA 19107

(215) 503-4511

Research & Clinical Interests

Breast cancer has a predilection for bone metastases, and is the second leading cause of cancer deaths in American women.  While the mechanism for directional metastasis is unknown, the bone microenvironment provides a fertile soil for breast cancer cells to colonize and grow.

Metastatic lesions are thought to originate from disseminated tumor cells (DTCs) shed from a primary tumor.  Clinical evidence suggests that, upon entry in a secondary niche, DTCs undergo proliferative quiescence for a period of up to 25 years, where they are capable of escaping immune surveillance and evading chemotherapeutic agents.  As a result, breast cancer patients successfully treated for primary breast cancer decades before suddenly develop overt macrometastases without prior symptoms.  This latency period before relapse at a secondary site can be defined as metastasis dormancy.  Thus, there is a critical need for elucidating the molecular mechanisms facilitating breast cancer dormancy and reactivation in the bone such that preventative therapeutics can be developed.  Despite the high prevalence of dormant tumors in humans, this area of cancer research is poorly understood and understudied.

The focus of Dr. Bussard’s research is two-fold: 1) identify microRNA, proteins, and novel mediators that facilitate cancer cell dissemination to bone, including mediators of cancer cell arrival and localization, as well as delineate conditions that orchestrate proliferative quiescence and cancer cell re-activation in bone.  Data generated in Dr. Bussard’s laboratory suggest that osteoblasts form gap junctions with metastasis-suppressed breast cancer cells, which may contribute to cellular crosstalk between the two cell types.  Bone osteoblasts were also found to produce exosomes which contain exosomal microRNAs found to be involved in cell cycle control and cellular dormancy.  These osteoblast-derived exosomes were taken up by breast cancer cells in a co-culture setting.

In parallel, 2) research in Dr. Bussard’s laboratory intends to elucidate the molecular basis of crosstalk between tumor cells and the host stroma, with a focus on understanding alterations in bone osteoblasts, that create a permissible environment for metastatic cancer cell colonization and survival.  Dr. Bussard has found that breast cancer cells cause osteoblasts to alter their production of matrix proteins, and increase their production of a set of inflammatory cytokines: IL-6, IL-8, MCP-1, and VEGF that mediate breast cancer cell maintenance and survival.  Combined, these data suggest that there is extensive crosstalk between osteoblasts and disseminated cancer cells in bone, and highlights the importance of investigating osteoblasts as key players which mediate cancer cell proliferative quiescence in bone.

Research in Dr. Bussard’s laboratory utilizes both 2D and 3D in-vitro cell culture models, high-end fluorescence microscopy, novel humanized mouse models of tumor development, and implantable hydrogel biomaterial scaffolds to examine interactions between cancer cells and the host stroma, with a focus on bone metastatic breast cancer.  Dr. Bussard is also the recipient of a NIH/NCI K99/R00 Pathway to Independence Award, which has been instrumental to establishing her research program.

Publications

Most Recent Peer-Reviewed Publications

  1. Understanding mitochondrial polymorphisms in cancer
  2. Mesenchymal Stem Cell Transition to Tumor-Associated Stromal Cells Contributes to Cancer Progression
  3. The Clock Is Ticking: Countdown to Metastases
  4. Tumor-associated stromal cells as key contributors to the tumor microenvironment
  5. Mesenchymal stem/stromal cell-targeted therapies for solid tumors and hematological malignancies
  6. Human Breast Cancer Cells Are Redirected to Mammary Epithelial Cells upon Interaction with the Regenerating Mammary Gland Microenvironment In-Vivo
  7. The influence of metastatic breast cancer on the bone microenvironment
  8. The mammary gland microenvironment directs progenitor cell fate in vivo
  9. Osteoblasts are a major source of inflammatory cytokines in the tumor microenvironment of bone metastatic breast cancer
  10. Immortalized, premalignant epithelial cell populations contain long-lived, label-retaining cells that asymmetrically divide and retain their template DNA
  11. Reprogramming human cancer cells in the mouse mammary gland
  12. Localization of osteoblast inflammatory cytokines MCP-1 and VEGF to the matrix of the trabecula of the femur, a target area for metastatic breast cancer cell colonization
  13. Ex-vivo analysis of the bone microenvironment in bone metastatic breast cancer
  14. The bone microenvironment in metastasis; what is special about bone?
  15. Metastatic breast cancer induces an osteoblast inflammatory response
  16. Kinetics of metastatic breast cancer cell trafficking in bone
  17. Mathematical modeling of material-induced blood plasma coagulation
  18. Procoagulant stimulus processing by the intrinsic pathway of blood plasma coagulation
  19. Effective production of FXIIa and thrombin by model biomaterials
  20. Effective production of FXIIa and thrombin by model biomaterials