Indiana University-Purdue University Indianapolis (IUPUI) / Neurofibromatosis type 2 (NF2) is an autosomal dominant cancer predisposition
in which loss of heterozygosity at the NF2 gene locus leads to the development of tumors
of neural crest derived origin, most commonly bilateral vestibular schwannomas. There
are currently no FDA approved chemotherapeutic agents for treatment in patients with
NF2. Development of therapeutic agents has been hampered by our incomplete
knowledge of how Merlin, the protein product of the NF2 gene, functions as a tumor
suppressor. In order develop a deeper understanding for how loss of Merlin leads to
oncogenic transformation in Schwann cells we have developed a genetically engineered
mouse model (GEMM) of Neurofibromatosis Type 2 in which functional expression of
Merlin is lost in Schwann cell precursors. In parallel studies utilizing these mice, we have
sought to understand the pathophysiology driving tumor formation in Merlin deficient
Schwann cells.
In Chapter 1, we explore the role of Merlin as a negative regulator of the Group A
p21 activated kinases, PAK1 and PAK2. We demonstrate that PAK1, a previously well
established oncogene in solid tumors and Merlin binding partner, is hyperactivated in
Merlin deficient schwannomas. Through therapeutic interventions and genetic
manipulations we demonstrate that inhibition of PAK1 was capable of reducing tumor
formation and alleviating sensorineural hearing loss in our NF2 GEMM.
In Chapter 2, we investigate the role of NF-kB inducing kinase (NIK) and NF-kB
signaling in the formation and growth of Merlin deficient Schwann cell tumors. Prior work in our lab as well as by others demonstrated elevated NF-kB signaling in Merlin
deficient Schwann cell tumors. We observed accumulation of a catalytically active
fragment of NF-kB inducing kinase and present data that accumulation of a 55Kd
constitutively active fragment of NIK is sufficient trigger wild type Schwann cells to
form tumors. In vivo however, Schwann cell intrinsic expression of NIK is not required
for tumor formation or growth. / 2 years (2021-05-24)
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/19638 |
| Date | 05 1900 |
| Creators | Hawley, Eric Thomas |
| Contributors | Clapp, D. Wade, Goebl, Mark G., Harrington, Maureen A., Mirmira, Raghu G. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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