Defining Molecular and Developmental Pathogenesis of Schwann Cell Tumors to Identify Therapeutic Targets
Abstract
Schwannoma develops in all NF2 and Schwannomatosis patients and can infiltrate the nerves, leading to neurological dysfunction such as deafness. In addition, patients with Schwannoma suffer from chronic pain, numbness, and their physical impairment of vital organ or neural function can be life-threatening. Despite the identification of NF2, INI1/SMARCB1 and newly identified Schwannomatosis-predisposing gene LZTR1, the exact molecular pathogenesis and dysregulated pathways causing Schwannoma development are still poorly understood. As such, there is currently no effective, specific medical treatment for these complex tumors. This research proposal will fill this gap to elucidate the mechanisms by which certain cancer pathways affect Schwannoma formation, as well as to generate potential specific therapeutic targets for Schwannomas. Recently, our lab conditionally knocked out Lats1/2 (effectors of the Hippo pathway) in the kidney using Hoxb7-Cre mice (kidney and neural crest specific Cre) to study kidney cancer. Serendipitously, we found that these mice develop extensive peripheral nerve tumors exhibiting all the histological and molecular features of human Schwannoma. This discovery indicates that deregulation of the Hippo pathway is critical for the initiation of Schwannoma development. Our novel mouse model for Schwannoma should also provide a useful and valuable experimental tool to investigate fundamental questions of Schwann cell tumor pathobiology and experimental therapeutics. In fact, it began to yield vital clues on biological events leading to Schwannoma development. In these tumor cells, we observed the inactivation of Hippo signaling pathway followed by activation of WNT/ -Catenin signaling pathway, and the dysregulation of both signaling pathways are critical for survival of Schwannoma cell lines. Most importantly, we also observed the deregulations of these two pathways in a panel of human schwannoma tissues, establishing a correlation with the human Schwannoma tumors and, therefore, the significance of this novel mouse model for the human disease. Based on these data, we hypothesize that both Hippo and WNT/ -Catenin signaling pathway may coordinate to regulate Schwannoma development and tumor cell survival. The central components of both signaling pathway may be attractive targets for drug development. Therefore, our proposed studies will further delineate the mechanisms of Schwannoma genesis, which will help us to better understand this disease as well as to develop specific therapies toward delaying or preventing the development of Schwannoma.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710148
Entities
People
- Lu Q Le
Organizations
- United States Army
- University of Texas Southwestern Medical Center