Loss of function mutations in the
neurofibromatosis Type 2 (NF2) gene, coding for a tumour suppressor,
Merlin, cause multiple tumours of the nervous system such as
schwannomas,
meningiomas and
ependymomas. These tumours may occur sporadically or as part of the hereditary condition
neurofibromatosis Type 2 (NF2). Current treatment is confined to (radio) surgery and no targeted
drug therapies exist. NF2 mutations and/or
Merlin inactivation are also seen in other
cancers including some
mesothelioma,
breast cancer,
colorectal carcinoma,
melanoma and
glioblastoma. To study the relationship between
Merlin deficiency and tumourigenesis, we have developed an in vitro model comprising human primary
schwannoma cells, the most common
Merlin-deficient tumour and the hallmark for NF2. Using this model, we show increased expression of cellular
prion protein (PrPC) in
schwannoma cells and tissues. In addition, a strong overexpression of PrPC is observed in human
Merlin-deficient
mesothelioma cell line TRA and in human
Merlin-deficient
meningiomas. PrPC contributes to increased proliferation, cell-matrix adhesion and survival in
schwannoma cells acting via 37/67 kDa non-
integrin laminin receptor (LR/37/67 kDa) and downstream ERK1/2, PI3K/AKT and FAK signalling pathways. PrPC
protein is also strongly released from
schwannoma cells via exosomes and as a free
peptide suggesting that it may act in an autocrine and/or paracrine manner. We suggest that PrPC and its interactor, LR/37/67 kDa, could be potential therapeutic targets for
schwannomas and other
Merlin-deficient tumours.