Neveen Said, MD, PhD
Identification of the differential roles of matricellular glycoprotein on modulating tissue homeostatsis
My primary interest is identification of the differential roles of matricellular glycoprotein (Secreted Protein Acidic and Rich in Cysteine, SPARC) on modulating tissue homeostasis. The main characteristic of this glycoprotein is that it is developmentally regulated and in adult life, mainly expressed during tissue renewal and repair in order to “normalize” the tissue microenvironment. I am specifically interested in its differential roles as positive and negative regulator of cell-cell, and cell-matrix interactions, in a given microenvironment, emphasizing on its differential roles in carcinogenesis, inflammation, tumor growth and metastasis, in urogenital cancers (bladder, and ovarian).
In ovarian cancer, I have identified that SPARC exerts tumor suppressor effect in serous ovarian cancer through its anti-proliferative, pro-apoptotic and an anti-adhesive effects on ovarian cancer cells. These effects of SPARC were mediated through its inhibition of integrin- and growth factor-mediated survival signaling pathways. On the other hand, tumor- and host-SPARC were found to play an important role in normalizing the reactive ovarian microenvironment through suppression of the transcriptional activity of the major orchestrator of inflammation NFĸB and STAT3. The long-term objectives is to understand the molecular mechanisms and signaling pathways implicated in the differential interactions of SPARC with the key cells that foster peritoneal ovarian carcinomatosis (mesothelial cells, macrophages, omental fibroblasts and adipocytes).
In bladder cancer, I am studying the differential roles of SPARC in urinary bladder carcinogenesis using a chemical carcinogensis SP-/- mice (and wild type counterparts). I am exploring its differential effects of SPARC on carcinogenesis on one aspect and on tumor-host interactions in the primary and metastatic milieus. The overall goal is understanding the stage-specific biological activities of SPARC, signaling pathways involved and identification of biomarkers in each phase of the disease that are modulated by SPARC and their diagnostic, prognostic and therapeutic implications.
Another aspect of my research interests is investigating the molecular mechanisms of bladder cancer metastasis and organotropism. Using carcinogen-induced, spontaneous and experimental metastasis models, as well as human clinical data, I have found that second to nodal metastases, bladder cancer cells preferentially metastasize to the lungs. Employing syngeneic murine cancer cells in immunocompetent/transgenic mice as well as genetically engineered human cancer cell lines in immunodeficient mice, I have recently identified the mechanisms of pro-metastasis effect of the peptide hormone Endothelin-1 and ECM proteoglycan Versican in the bidirectional crosstalk between cancer cells and macrophages promoting pulmonary inflammation and metastatic colonization of bladder cancer cells in the lungs. I have developed and employed 2-D and 3-D cell culture systems, and co-culture systems to investigate cell-cell interactions within lung microenvironment. I am employing genetic, proteomic, and pharmacologic approaches to modulate these interactions in vitro, ex vivo and in vivo. Given the roles of versican and endothelin in a variety of vascular morbidities; specifically in pulmonary vasculopathies, and their indispensible roles in pulmonary and cardiovascular development, a more complete understanding of common pathways implicated in pulmonary vascular diseases and cancer has the potential to greatly improve treatment and overall survival for a wide range of indolent metastatic cancers. Unraveling the importance of these molecules will provide intriguing insights into the molecular mechanisms of seemingly unrelated phenomena.