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Timing of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development
Jeremie Vitte1, Fuying Gao2, Giovanni Coppola2
1Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles, Los Angeles, CA, 90095, USA.
Abstract:
Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes: rhabdoid tumor predisposition syndrome, with malignant pediatric tumors mostly developing in brain and kidney, and familial schwannomatosis, with adulthood benign tumors involving cranial and peripheral nerves. The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors versus schwannomas are still unknown. Here, to understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue- and developmental stage-specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion. Smarcb1 loss in early neural crest was necessary to initiate tumorigenesis in the cranial nerves and meninges with typical histological features and molecular profiles of human rhabdoid tumors. By inducing Smarcb1 loss at later developmental stage in the Schwann cell lineage, in addition to biallelic Nf2 gene inactivation, we generated the first mouse model developing schwannomas with the same underlying gene mutations found in schwannomatosis patients. SMARCB1 mutations predispose to rhabdoid tumors and schwannomas but the mechanisms underlying the tumor type specificity are unknown. Here the authors present new mouse models and show that early Smarcb1 loss causes rhabdoid tumors whereas loss at later stages combined with Nf2 gene inactivation causes shwannomas.
Insights
Germline mutations in the SMARCB1 gene cause rhabdoid tumors and schwannomatosis. Early Smarcb1 loss leads to rhabdoid tumors, while later loss with Nf2 inactivation causes schwannomas in new mouse models.
Area of Science:
- Oncology
- Genetics
- Developmental Biology
Background:
- Germline mutations in the SMARCB1 gene are associated with rhabdoid tumor predisposition syndrome and familial schwannomatosis.
- The distinct tumor types arising from SMARCB1 mutations suggest complex regulatory mechanisms.
- Understanding the basis for tumor type specificity in SMARCB1-associated syndromes is crucial.
Purpose of the Study:
- To investigate the mechanisms underlying tumor type specificity in SMARCB1-associated syndromes.
- To generate and characterize novel mouse models for studying rhabdoid tumors and schwannomas.
Main Methods:
- Generation of tissue- and developmental stage-specific conditional knockout mice with Smarcb1 and/or Nf2 deletion.
- Analysis of tumor initiation and development in response to Smarcb1 loss at different developmental stages.
- Histological and molecular profiling of tumors to compare with human disease.
Main Results:
- Early Smarcb1 loss in neural crest cells initiated tumorigenesis in cranial nerves and meninges, mirroring human rhabdoid tumors.
- Induction of Smarcb1 loss at later developmental stages in Schwann cells, combined with biallelic Nf2 inactivation, generated a novel mouse model for schwannomas.
- This study provides the first mouse models that replicate the specific genetic underpinnings of schwannomatosis.
Conclusions:
- Tumor type specificity in SMARCB1-associated syndromes is dependent on the timing of Smarcb1 loss during development.
- Early Smarcb1 loss drives rhabdoid tumor formation, whereas later loss with Nf2 inactivation promotes schwannoma development.
- These findings elucidate the distinct origins of rhabdoid tumors and schwannomas and offer valuable models for future research.
