The transforming growth factor beta (TGF-?) signaling pathway regulates the development and function of the peripheral nervous system and has a significant role in the pathogenesis of the pediatric cancer, neuroblastoma (NB). TGF-? ligands have been shown to promote neuritogenesis and neuronal differentiation of NB cells in vitro. The type III TGF-? receptor (T?RIII) is a transmembrane proteoglycan which undergoes ectodomain shedding, releasing a soluble receptor form (sT?RIII). T?RIII acts as a co-receptor in the TGF-? signaling pathway, regulating TGF-? ligand bioavailability to mediate canonical activation of TGF-?-stimulated transcription factors. T?RIII also has TGF-? signaling-independent roles in regulating cell proliferation, migration and invasion. Decreased T?RIII expression has been reported in the progression of several adult cancers and has been associated with advanced-stage NB. Microarray dataset analysis demonstrates a decrease in T?RIII expression in malignant NB compared with benign ganglioneuroblastoma and ganglioneuroma. This analysis also reveals that T?RIII expression positively correlates with tumor stromal content, which is associated with improved clinical prognosis. Consistent with this result, we observe expression of T?RIII in the stroma of NB clinical specimens. In preliminary in vitro data, we demonstrate that restoration of T?RIII expression or treatment with sT?RIII promotes neuritogenesis and neuronal differentiation in a cell line model of NB. sT?RIII released from a Schwannian stromal cell line also has neuritogenic and differentiating effects on neuroblastic cells of the same lineage. While sT?RIII has been characterized as an inhibitor of TGF-? signaling, functioning via ligand sequestration, the ability of sT?RIII to mimic the effect o TGF-? ligands suggests a novel mechanism for sT?RIII function. Elucidating the molecular mechanisms directing sT?RIII's effects on NB tumor cell differentiation will aid in identifying therapeutic targets for this devastating pediatric cancer. Based on our preliminary data and the defined role of TGF-? signaling in neuronal differentiation and NB pathogenesis, we hypothesize that sT?RIII released by the stroma promotes neuronal differentiation via canonical TGF-? signaling to inhibit NB invasiveness.
The goal of my research is to determine whether the soluble type III TGF-? receptor, when released from the tumor stroma, increases neuroblastoma cell differentiation to suppress tumor invasiveness, and the mechanism by which this occurs. Elucidating this mechanism will aid in identifying therapeutic targets for this devastating pediatric cancer.
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