PT  - JOURNAL ARTICLE
AU  - Chiasson-MacKenzie, Christine
AU  - Vitte, Jeremie
AU  - Liu, Ching-Hui
AU  - Wright, Emily A.
AU  - Flynn, Elizabeth A.
AU  - Stott, Shannon L.
AU  - Giovannini, Marco
AU  - McClatchey, Andrea I.
TI  - Cellular mechanisms of heterogeneity in <em>NF2</em>-mutant schwannoma
AID  - 10.1101/2020.12.31.424999
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2020.12.31.424999
4099  - http://biorxiv.org/content/early/2023/01/23/2020.12.31.424999.short
4100  - http://biorxiv.org/content/early/2023/01/23/2020.12.31.424999.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-/- Schwann cells to adopt distinct programs of coordinated ErbB ligand production and polarized signaling, suggesting a self-generated model of schwannoma heterogeneity. We validated the heterogeneous distribution of biomarkers of these programs in human schwannoma tissue and took advantage of the synchronous development of multiple lesions in a well-studied mouse model to establish a quantitative pipeline that can be used to study how schwannoma heterogeneity evolves and impacts nerve function and therapeutic response in mouse, and ultimately human schwannomas. Our studies inform a mounting appreciation that intrinsic mechanisms are major contributors to heterogeneity across many human cancers.Competing Interest StatementThe authors have declared no competing interest.