We carried out two large screens to identify genes driving MPNST formation or maintenance: 1) An shRNA screen in human MPNST cell lines, and 2) a Sleeping Beauty (SB) transposon- based insertional mutagenesis screen in a mouse model of MPNST. Both research approaches identified Wnt/?atenin-regulated pathways as critical mediators of MPNST maintenance. Preliminary data confirms that the Wnt/?atenin pathway is required for MPNST maintenance and can be targeted using small molecules. Remarkably, we identified multiple mechanisms of activation of ?atenin that operate in MPNST. Our proposal focuses on these.
Aim 1 is based on our data demonstrating that genetic or pharmacological activation of the ?atenin destruction complex reduce ?atenin levels, reduce target gene expression, and inhibit cell survival and proliferation in MPNST.
Aim 2 is based on data showing that some MPNSTs ectopically express a Wnt/?atenin activator R-spondin 2 (RSPO2) due to transcript fusion with the upstream EIF3E gene, a mechanism we recently identified in human colorectal cancer.
Aim 3 is based on data revealing that the ?atenin target gene PITX2 plays a critical role in MPNST cell survival. Our goals are two-fold: to define the molecular landscape of ?atenin de- regulation in MPNST, and perform a thorough pre-clinical evaluation of critical targets for intervention in the Wnt/?atenin pathway in MPNST, setting the stage for effective clinical testing in human patients. The Co-PIs have established a successful collaborative relationship built on complementary skills and resources. Abundant and orthogonal preliminary data support the basic hypothesis of this proposal.

Public Health Relevance

This proposal describes work done in mice to understand how certain tumors of the peripheral nerves, called malignant peripheral nerve sheath tumors (MPNST), develop. We have discovered a new mechanism that causes these tumors - called beta-catenin signaling. This is a dangerous form of cancer and new treatments are needed. Metastatic MPNST has a dismal prognosis. Only surgery, radiation and conventional chemotherapy are currently available. We will target beta-catenin for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS086219-05
Application #
9532961
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Morris, Jill A
Project Start
2014-08-15
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Wu, Lai Man Natalie; Deng, Yaqi; Wang, Jincheng et al. (2018) Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell 33:292-308.e7
Wu, J; Liu, W; Williams, J P et al. (2017) EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation. Oncogene 36:1669-1677
Currier, Mark A; Sprague, Les; Rizvi, Tilat A et al. (2017) Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation. Oncotarget 8:17412-17427
Dombi, Eva; Baldwin, Andrea; Marcus, Leigh J et al. (2016) Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med 375:2550-2560
Wu, Jianqiang; Keng, Vincent W; Patmore, Deanna M et al. (2016) Insertional Mutagenesis Identifies a STAT3/Arid1b/?-catenin Pathway Driving Neurofibroma Initiation. Cell Rep 14:1979-90
Patel, Ami V; Chaney, Katherine E; Choi, Kwangmin et al. (2016) An ShRNA Screen Identifies MEIS1 as a Driver of Malignant Peripheral Nerve Sheath Tumors. EBioMedicine 9:110-119
Sachs, Zohar; Been, Raha A; DeCoursin, Krista J et al. (2016) Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency. Haematologica 101:1190-1199
Kendall, Jed J; Chaney, Katherine E; Patel, Ami V et al. (2016) CK2 blockade causes MPNST cell apoptosis and promotes degradation of ?-catenin. Oncotarget 7:53191-53203