Mike and Josie Harper Cancer Research Institute
M. Sharon Stack
Professor, Chemistry & Biochemistry
Ann F. Dunne and Elizabeth Riley Science Director, Harper Cancer Research Institute
University of Notre Dame
The ability to invade host tissues and metastasize is the major cause of cancer-related death. During tumor invasion, metastasizing cells disrupt normal cell-cell and cell-matrix contacts and acquire a migratory, invasive phenotype. Thus modulation of cell-cell and cell-matrix adhesive events likely plays a critical role in tissue remodeling during tumor progression. Subsequent alterations in cellular architecture mediated by modified extracellular matrix (ECM) attachments induce expression of proteinases that degrade ECM proteins, facilitating migration through the modified tissue to establish metastatic foci and removing matrix constraints that normally limit proliferation. Although malignant cells produce a spectrum of matrix-degrading enzymes, predominant among these proteinases are enzymes in the plasminogen activator (PA) and matrix metalloproteinase (MMP) families. Current research centers on regulation of these proteinase families in two model systems: epithelial ovarian carcinoma and squamous cell carcinoma of the oral cavity. Ongoing research utilizes an integrative approach involving examination of 2-dimensional (2D) and 3D tissue culture systems and organotypic cultures complemented by murine tumor models and analyses of human tumors. Understanding the molecular mechanisms by which tumor cells orchestrate multiple microenvironmental cues to regulate the expression and activity of metastasis-associated proteinases is the major focus of the laboratory.
Additional collaborative research with Dr. Laurie Hudson (Univ. of New Mexico) is examining areas of convergence between epidermal growth factor receptor (EGFR) and cell adhesion (cadherin and integrin) signaling pathways in ovarian carcinoma metastatic dissemination. Collaborative research with Dr. Matthew Ravosa (Univ. of Missouri) focuses on the relationship between mechanical loading and tissue remodeling in development and ageing of the masticatory apparatus.
