Investigation of a novel molecular driver of schwannoma nerve sheath tumors - PROJECT SUMMARY: Schwannomas are the most common sporadic nerve sheath tumor which arise from the Schwann cells that ensheathe and insulate axons of the peripheral nervous system. Schwannomas can cause significant morbidity depending on location and adjacent structures that are compressed over time, particularly those involving cranial nerves such as hearing loss for vestibular nerve tumors. Complete resection can be curative, but may result in permanent nerve injury. Furthermore, resection is not always possible depending on tumor location that can result in recurrence and progression over time, necessitating additional surgery or radiation therapy for disease control and symptom management. Thus, there is a pressing clinical need for more efficacious treatment options. While studying schwannomas arising in the setting of known predisposition syndromes due to germline mutations involving NF2, LZTR1, and SMARCB1 has shed substantial light on schwannoma pathogenesis, the molecular drivers responsible for sporadic schwannomas have not been fully resolved to date. Through genomic profiling studies, we discovered that 22/77 (29%) of sporadic schwannomas lack alterations in known schwannoma-associated genes and instead harbor recurrent in-frame insertions or deletions in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation. These insertions/deletions are uniformly somatic (tumor-acquired) and localize at the C-terminal end of the HMG box domain responsible for DNA binding. Our preliminary analysis has revealed that schwannomas harboring SOX10 indel mutations often occur along paraspinal and non-vestibular cranial nerves and have high local recurrence rates. Based on our identification of recurrent SOX10 indel mutations within the DNA binding domain, we hypothesize these mutations are likely to drive schwannoma development through altered chromatin binding and transcriptional reprogramming that blocks terminal differentiation of immature Schwann cells resulting in a persistent progenitor-like state. To test this hypothesis, we propose three aims utilizing our unique cohort of clinically annotated and molecularly-genotyped human schwannoma tumor specimens, primary human schwannoma cultures and Schwann cell models with wildtype or tumor- derived mutant SOX10 alleles, and a conditional Sox10flox-K172_Y173dup knock-in mutant mouse strain we have generated. In Aim #1, we will perform multi-omic profiling to determine whether SOX10 mutation defines a unique subtype of schwannoma with distinct histopathologic, transcriptomic, epigenomic, and cellular features. In Aim #2, we will evaluate whether tumor-derived SOX10 mutations result in altered chromatin binding and transcriptional reprogramming. In Aim #3, we will investigate whether SOX10 indel mutations are sufficient and necessary to drive schwannoma growth and explore potential therapeutic vulnerabilities of SOX10 mutant schwannomas. Together, these studies aim to reveal fundamental properties of Schwann cell differentiation and pinpoint the tumorigenic mechanism of a substantial fraction of clinically aggressive schwannomas.
