All ETDs from UAB

Advisory Committee Chair

Ralph Sanderson

Advisory Committee Members

James Collawn

Douglas Hurst

Christopher Klug

Elizabeth Sztul

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

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.

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