Schwannomatosis tumor modeling: progress and prospects for translational research

BACKGROUND: Schwannomatosis (SWN) is a rare genetic condition characterized by the development of benign schwannomas along peripheral and spinal nerves, and this tumor development often results in chronic peripheral pain and significant neurological deficits. Despite surgical resection being the current standard of care for SWN-related pain, scientists are searching for accurate preclinical models that can be used for drug efficacy testing, but existing models often fail to fully recapitulate the complex genotypic diversity and tumor-nerve interface pathology seen in patients. MAIN TEXT: This review first summarizes the genotypic and phenotypic characteristics of SWN subtypes resulting from key mutations in NF2, SMARCB1, LZTR1, and other chromosome 22q-related genes. Then, it provides a comprehensive overview of current preclinical frameworks for schwannomatosis including cell lines, mouse xenografts, and genetically engineered mouse models. We critically evaluate the respective strengths and limitations of each framework in modeling disease pathogenesis. Specifically, this review examines how the conventional two-dimensional culture systems inadequately represent the three-dimensional tumor architecture and interactions found between schwannoma cells, nerve fibers, and surrounding structural components. Next, this review highlights emerging preclinical platforms such as patient-derived organoids, SWN-on-chip microfluidic systems, and more advanced microphysiological systems that integrate cellular compartments to better simulate the tumor microenvironment. Moreover, we analyze the inclusion of large animal models to improve the fidelity and clinical relevance of SWN investigation, particularly in their potential to recapitulate human-scale anatomy and immune responses, for future therapeutic testing and discovery. CONCLUSION: Current preclinical approaches for schwannomatosis rely on commercial and patient-derived cells and small-animal models, which we discuss in this review. The emergence of advanced platforms such as SWN-on-chip bioengineered systems and large animal models represents a critical evolution in preclinical modeling capabilities, offering more physiologically relevant frameworks for mechanistic investigation and translational therapeutic evaluations. Bridging the gap between these evolving preclinical systems and clinical outcomes will require continued refinement of models that faithfully reproduce the tumor-nerve interface pathology and genotype-phenotype relationships observed in patients.