PT  - JOURNAL ARTICLE
AU  - Christine Chiasson-MacKenzie
AU  - Ching-Hui Liu
AU  - Jeremie Vitte
AU  - Marco Giovannini
AU  - Andrea I. McClatchey
TI  - Cellular mechanisms of heterogeneity in <em>NF2</em>-mutant schwannoma
AID  - 10.1101/2020.12.31.424999
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.12.31.424999
4099  - http://biorxiv.org/content/early/2021/01/03/2020.12.31.424999.short
4100  - http://biorxiv.org/content/early/2021/01/03/2020.12.31.424999.full
AB  - Schwannomas are common sporadic nervous system tumors and diagnostic features of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves and cause severe neurological deficits and significant morbidity. Virtually all schwannomas result from inactivation of the NF2 tumor suppressor gene with few, if any, cooperating mutations. Despite their genetic uniformity schwannomas exhibit remarkable clinical and therapeutic heterogeneity, which has impeded the success of early rational therapies. An understanding of how heterogeneity develops in NF2-mutant schwannomas is critically needed to improve therapeutic options for these patients. We have found that loss of the membrane:actin cytoskeleton-associated NF2 tumor suppressor protein, merlin, yields unstable intrinsic polarity and enables Nf2-/- SCs to adopt distinct programs of coordinated autocrine ErbB ligand production, polarized signaling and metabolism according to nutrient availability. We validated biomarkers of these programs in a well-established mouse model of schwannoma. Our studies suggest a self-generating model of heterogeneity and identify biomarkers that can now be mapped to the variable clinical and therapeutic behaviors of human schwannomas.Competing Interest StatementThe authors have declared no competing interest.