Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive cancers that arise in 10% of young adults with Neurofibromatosis type 1 (NF1). Despite aggressive chemotherapy and radiation, the prognosis for these cancers remains dismal. In order to better understand why these tumors form and how they can be best treated, several small-animal models of MPNSTs have developed. However, none of these models accurately model the order of genetic changes in these cancers, nor the symptoms that affected individuals frequently experience.
Using a combination of novel genetically-engineered mice and viral gene silencing approaches, Dr. Angela Hirbe and her colleagues in the Washington University NF Center, created a new model in which the order of genetic changes can be controlled. Moreover, these mice start to limp when these cancers form. This advance was possible because of a unique collaboration between Dr. Hirbe and Dr. Sonika Dahiya at Washington University, Dr. Wade Clapp at Indiana University, and Drs. Dinorah Friedmann-Morvinski and Inder Verma at the Salk Institute.
Dr. Hirbe plans to use this new model to discover and evaluate new drugs to treat these deadly cancers.
MPNST formation is accelerated in Nf1+/- mice harboring embryonic Nf1 loss and somatic Trp53 reduction. Depicted here are gross images of the sciatic nerves from GFAP-Cre; Nf1flox/null mice injected with vehicle or pTomo-shNf1;shp53 virus. Low-grade MPNSTs were only observed in the sciatic nerves of GFAP-Cre; Nf1flox/null mice injected with pTomo-shNf1;shp53 virus. Scale bar, 1000µm.
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Hirbe AC, Dahiya S, Friedmann-Morvinski D, Verma IM, Clapp DW, Gutmann DH. Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation. Oncotarget. 2016 Feb 7. doi: 10.18632/oncotarget.7232. [Epub ahead of print]