All ETDs from UAB

Advisory Committee Chair

Steven L Carroll

Advisory Committee Members

Rita Cowell

G Yancey Gillespie

Douglas Hurst

Robert Kesterson

David Sweatt

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in patients with neurofibromatosis type-1. These aggressive, Schwann cell-derived tumors have no treatment beyond surgical resection. Developing targeted chemotherapeutics remains crucial to improving patient survival. The Schwann cell mitogen neuregulin-1 (NRG1) was shown to mediate the migration, proliferation and survival of MPNSTs. Furthermore, overexpression of NRG1 in Schwann cells (P0-GGF beta 3 mice) on an outbred C57BL/6J x SJL/J background induced the formation of neurofibromas and MPNSTs similar to human disease, yet these mice have intact neurofibromin. To determine if NRG1 acts within the same signaling cascade as neurofibromin loss or within parallel signaling cascades, we performed genetic complementation assays with inbred P0-GGFbeta3 mice on a C57BL/6J background, which no longer develop tumors, but maintain transgene expression. These animals were then bred to Nf1+/- or Trp53+/- mice and monitored for rescue of tumorigenesis. Much like Nf1+/-; Trp53+/- mice, P0-GGF beta 3; Trp53+/- mice developed de novo MPNSTs, suggesting that NRG1 overexpression acts within the same cascade as neurofibromin loss. NRG1 signals via erbB3 and erbB4 receptors, which are part of the erbB family of receptor tyrosine kinases (RTKs). While erbB3 is crucial for Schwann cell development, erbB4 is never expressed in these cells. The expression of erbB4 in MPNSTs suggests a unique role for this receptor in tumor pathogenesis. We developed P0-GGF beta 3; Trp53+/-; ErbB4flox/flox mice to examine this role. Ablation of erbB4 in vivo via adenoviral-mediated Cre recombinase resulted in decreased tumor volume, decreased proliferative indices, and increased apoptosis compared to tumors expressing erbB4. Knockdown of erbB4 in human tumor cells produced parallel results, suggesting that our mouse model adequately mimics human disease. ErbB4 activity contributed to numerous cytoplasmic signaling cascades and nuclear signaling. To determine if other RTKs contribute to MPNST development, we globally profiled RTK activity. Multiple RTKs were co-activated within MPNSTs, though only erbB receptors, insulin-like growth factor receptor, and Trk family receptor inhibition decreased proliferation of four human MPNST cell lines. Monotherapy with inhibitors against these receptors was largely cytostatic, while combinatorial treatment was cytotoxic and led to marked decreases in downstream signaling cascades such as Ras and Erk. Considered collectively, these data indicate that dysregulated growth factor signaling plays an important role in MPNSTs pathogenesis and may provide viable targets for chemotherapy.

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