Interests of the laboratory are focused on breast cancer and the role of lysosomal trafficking in tumor growth and metastasis. Intracellular trafficking of lysosomal proteins in mammalian cells and tissues is mediated by the mannose 6-phosphate recognition system. This system is responsible for construction of mannose 6-phosphate residues on carbohydrate chains of lysosomal proteins and for translocating these proteins to the lysosomal compartment via mannose 6-phoshate receptors. Secretion of cathepsins and other lysosomal hydrolases resulting from altered interaction with mannose 6-phosphate receptors plays an important role tumor metastasis. In addition, mannose 6-phosphate/IGF-2 receptor, the receptor that plays the primary role in lysosomal trafficking, is a tumor suppressor gene for a wide range of cancers in man and rodents. A primary goal of the laboratory is determine the basis for the involvement of cathepsins and the receptor in the development and progression of cancer.

Previous accomplishments of the laboratory include isolation and characterization of the mannose 6-phosphate/IGF-2 receptor, analysis of the molecular basis for mannose phosphorylation of lysosomal proteins, and studies on the regulation of lysosomal trafficking by growth factors and oncogenes. Over the past two years, the laboratory has been developing novel mouse models for the study of tumor growth and metastasis in vivo. These models utilize newly emerging optical imaging methods for visualizing tumor cells in vivo and are optimized for use of microarray, RNAi and gene targeting technology to identify novel cancer-related genes and to study the roles of these genes in tumor growth and metastasis. These models are currently being used to investigate the involvement of lysosomal hydrolases and receptors in tumor growth and metastasis and to identify genes involved in organ-selective metastasis to lungs, liver, bone and brain, the primary organs affected by metastasis in breast cancer and other human malignancies.

Current research projects of the laboratory include the following:

• Molecular Basis for Mannose Phosphorylation of Lysosomal Proteins
• Mannose 6-Phosphate/IGF-2 Receptor – A Novel Tumor Suppressor Gene
• In Vivo Imaging and Analysis of Genes Involved in Organ-selective Metastasis

The Sahagian Lab operates the Tufts/NEMC Small Animal Imaging Facility.