Clapp, D. W. | bioRxiv Science

bioRxiv2024

A novel induced pluripotent stem cell model of schwann cell differentiation reveals NF2-related gene regulatory networks of the extracellular matrix

Schwann cells are vital to development and maintenance of the peripheral nervous system and their dysfunction has been implicated in a range of neurological and neoplastic disorders, including NF2-related schwannomatosis. We developed a novel human induced pluripotent stem cell (hiPSC) model to study Schwann cell differentiation in health and disease. We performed transcriptomic, immunofluorescence, and morphological analysis of hiPSC derived Schwann cell precursors (SPCs) and terminally differentiated Schwann cells (SCs) representing distinct stages of development. To validate our findings, we performed integrated, cross-species analyses across multiple external datasets at bulk and single cell resolution. Our hiPSC model of Schwann cell development shared overlapping gene expression signatures with human amniotic mesenchymal stem cell (hAMSCs) derived SCs and in vivo mouse models, but also revealed unique features that may reflect species-specific aspects of Schwann cell biology. Moreover, we identified gene co-expression modules that are dynamically regulated during hiPSC to SC differentiation associated with ear and neural development, cell fate determination, the NF2 gene, and extracellular matrix (ECM) organization. By cross-referencing results between multiple datasets, we identified new genes potentially associated with NF2 expression. Our hiPSC model further provides a tractable platform for studying Schwann cell development in the context of human disease.

bioinformatics↗

bioRxiv2022

Dual inhibition of SHP2 and autophagy suppresses NF1-associated Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). MPNSTs develop within pre-existing benign plexiform neurofibromas (PNs). PNs are driven solely by biallelic NF1 loss eliciting RAS pathway activation and respond favorably to MEK inhibitor therapy. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST indicates that MEK inhibition has poor anti-tumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors was performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining pharmacological blockade of autophagy and SHP2 inhibition resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies can be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with autophagy inhibitors as a novel treatment approach for NF1 MPNSTs. Statement of significanceCurrently, no effective therapies exist for MPNST. We demonstrate intrinsic MPNST resistance to MEKi monotherapy and identify SHP2 inhibition as an actionable vulnerability upstream of RAS. Furthermore, anti-tumor effects are extended and enhanced by dual exposure to autophagy pathway inhibition. Validation of these results as the most effective therapy to date in multiple genetically engineered models and in orthotopic patient-derived xenografts justify a clinical trial to evaluate SHP2i in conjunction with autophagy inhibitors as a novel treatment approach for NF1 MPNSTs.

cancer biology↗