Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Multiple myeloma is a hematological malignancy of plasma cells that disseminates throughout the body. Crosstalk between myeloma and host cells is critical to the establishment of a microenvironment conducive to tumor growth and progression. An important mediator of this crosstalk is syndecan-1, a heparan sulfate proteoglycan. Syndecan-1 is proteolytically shed from the surface of myeloma cells and is abundant in the bone marrow microenvironment and serum of myeloma patients. Shed syndecan-1 facilitates tumor-host crosstalk within the microenvironment to drive tumor growth, angiogenesis, and metastasis. We now report for the first time that shed syndecan-1 can be taken up by a recipient cell and transported to the nucleus. This was discovered by incubating bone marrow-derived stromal cells with medium conditioned by myeloma cells producing high levels of shed syndecan-1. Importantly, shed syndecan-1 is detected in the nucleus as early as 15 minutes after addition of medium containing shed syndecan-1 to cells. Translocation of shed syndecan-1 to the nucleus of the stromal cells required the sulfated heparan sulfate chains of syndecan-1 and addition of heparin or heparan sulfate blocked shed syndecan-1 transport to the nucleus. Interestingly, cargo such as hepatocyte growth factor (HGF) bound to shed syndecan-1 heparan sulfate chains was transported to the nucleus along with shed syndecan-1 and removal of heparan sulfate-bound cargo from shed syndecan-1 abolished its translocation to the nucleus of stromal cells. Once in the nucleus, shed syndecan-1 reduced histone acetyltransferase (HAT) activity and interacted directly with the HAT enzyme p300. Overall these results reveal a novel mechanism of tumor-host crosstalk whereby tumor-derived shed syndecan-1 disrupts nuclear functions in stromal cells which may lead to altered gene expression and abnormal cell behavior. Therapeutic regulation of syndecan-1 shedding, its binding to the cell surface or translocation to the nucleus represent novel strategies to control the progression of myeloma and other cancers.
Stewart, Mark, "Translocation of Shed Syndecan-1 to the Nucleus: A Novel Mechanism of Tumor-Host Crosstalk" (2014). All ETDs from UAB. 3045.