Loss of VPS4B function promotes tumorigenesis in osteosarcoma by altering the endosomal degradative pathway and leading to accumulation of activated EGFR

Marc Hansen

Marc Hansen

Professor

University of Connecticut Health Center

My laboratory is interested in the discovery and analysis of genetic pathways involved in the etiology of two diseases, osteosarcoma and Paget Disease of Bone. Based on phenotypic differences there is strong evidence that primary osteosarcoma of the appendicular skeleton and primary osteosarcoma of the craniofacial skeleton represent separate and distinct diseases. Allelotype analysis identified 13 chromosomal arms with significantly different frequencies of tumor-specific loss of constitutional heterozygosity (LoH) with eight chromosomal arms showed greater frequency of LoH in craniofacial osteosarcoma and five showed greater frequency of LoH in appendicular osteosarcomas. Comparative microarray analysis of craniofacial and appendicular osteosarcomas also revealed significantly different patterns of genomic expression patterns in the two types of osteosarcoma. It is possible that the phenotypic differences between craniofacial and appendicular osteosarcoma are in part due to the differences in the development derivation of the cells from which they originate. By examining the underlying genetic basis for craniofacial osteosarcoma and contrasting it with what is known of the genetic etiology of appendicular osteosarcoma, we may gain insight into tumorigenic pathways that unite or separate these two bone tumors of distinct embryonic origin. Paget’s Disease of Bone (PDB) is a focal disorder of bone remodeling that leads to overgrowth of affected bone, which in rare cases progresses to osteosarcoma. It is the second most common metabolic bone disease after osteoporosis. Two predisposing factors have been identified in PDB: 1) Studies of the association of measles virus or other paramyxoviruses with PDB have implicated expression of the measles virus nucleocapsid protein (MVNP) in the development of the pagetic phenotype and 2) Studies of the genetics of familial PDB that have identified a number of predisposing loci, with approximately 40% of the familial cases linked to the Sequestosome 1 (SQSTM1) gene on human chromosome 5q35. Our hypothesis is that PDB arises as the result of a combination of somatic mutations and environmental events that give rise to the pagetic lesion. We have chosen to focus on the genetic events that give rise to sporadic PDB and the potential role of somatic mutation in the affected tissues of patients to see if there is a progression of genetic events that give rise to PDB. We are now testing the subset of cells that contain the SQSTM1 mutation to see whether they act to recruit normal bone cells to the pagetic lesion and whether the osteosarcomas that arise within the pagetic bone arise from this subset of cells or whether the tumors arise simply as a result of increased bone turnover activity. Finally, we are examining the role of a tumor suppressor gene initially discovered in our screen of osteosarcoma tumors in the development of acquired resistance to the cancer drug Trastuzumab (Herceptin®) in women with advanced breast cancer. We found that in a majority of osteosarcomas there was a correlation between absence of expression of VPS4B and overexpression of erbB2 and EGFR in primary osteosarcoma tumors. This accumulation of EGFR and other receptors appears to be due to inhibition of both recycling of the activated receptors to the plasma membrane and degradation of the receptors via transport to the lysosomes and leads to prolonged signaling by the activated receptors. This internal accumulation of activated growth factor receptors may have implications for therapeutic strategies, as many new drugs targeted against growth factor receptors in cancer cells either depend on access to the target at the cell surface, or in some cases act through targeting the activated receptor to the endosomal degradative pathway. The determination of alternative genetic mechanisms by which breast cancer cells develop resistance to Herceptin® and strategies with which to treat these resistant newly tumors has the potential to have an impact on a significant fraction of women with breast cancer.

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