New paper #1!

Neurofibromin (NF1) is a large tumor suppressor best known for restraining Map kinase signaling, although it has many other roles as well. Germline mutation of one copy of NF1 causes one of the most frequent genetic disorders, neurofibromatosis type 1. Individuals with this disorder are plagued with multiple disfiguring tumors, called cutaneous neurofibromas, and are at risk of malignant transformation of the deeper plexiform neurofibromas. Attempts at knocking out Nf1 in mice have produced mostly paraspinal lesions, but not tumors really resembling typical cutaneous neurofibroma.

In addition, the NF1 gene is somatically hit in cutaneous melanomas, often in combination with other MAPK pathway activators. We were interested in whether the loss of NF1 in combination with GNAQ activation would accelerate the formation of non-cutaneous melanomas that form in the dermis and eyes (uveal melanoma). Our search of cancer databases and the literature had showed that deletion including the NF1 locus was a recurrent phenomenon in these tumor types, including one really interesting case in the TCGA cancer genome database that also has a RASA2 mutation. We have a mouse model that force expresses the human GNAQ oncogene, which drives the formation of non-cutaneous melanomas when expressed in melanocytes. Therefore, we crossed a conditional Nf1 allele onto our mouse model and analysed tumorigenesis using histology, immunohistochemistry, and RNAseq.

Indeed, we observed accelerated tumorigenesis in dermal and uveal melanomas in the Nf1 mutant mice. We found the RNAseq results very specific and interesting. As one example, there was a very significant signal for myogenesis among the down-regulated genes in Nf1 mutant uveal melanomas. As it turns out, people with myotonic dystrophy develop a significantly elevated number of various types of cancers. One study even found a 28-fold increased risk of uveal melanoma in people with myotonic dystrophy type 1. Furthermore, the down-regulated COX6A muscle gene was very significantly associated with worse uveal melanoma patient survival (p=1.7×10^-5) in the TCGA dataset.

In another unexpected twist, the mice developed peripheral nerve sheath tumors that strongly resembled human cutaneous neurofibromas. We didn’t want to assume too much, so we have been calling them “sparse pigment tumors.” These most likely arose because we used a Cre line expressed in both Schwann cells and melanocytes for conditional mutagenesis. We observed sparse pigment tumors on the trunk in about one-third of the mice and one mouse presented with a large plexiform variant  in the armpit region. These findings show for the first time that GNAQ can transform Schwann cells in mice (even without Nf1 loss).  This is yet another curious link between Schwann cells and melanocytes, which are both produced from the neural crest.