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Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.

ABSTRACT: Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. 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 successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found that loss of the membrane:cytoskeleton-associated NF2 tumor suppressor, merlin, yields unstable intrinsic polarity and enables Nf2^-/- Schwann cells to adopt distinct programs of 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 and exploited the synchronous development of lesions in a mouse model to establish a quantitative pipeline for studying how schwannoma heterogeneity evolves. Our studies highlight the importance of intrinsic mechanisms of heterogeneity across human cancers.

SUBMITTER: Chiasson-MacKenzie C

PROVIDER: S-EPMC10030849 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.

Chiasson-MacKenzie Christine C Vitte Jeremie J Liu Ching-Hui CH Wright Emily A EA Flynn Elizabeth A EA Stott Shannon L SL Giovannini Marco M McClatchey Andrea I AI

Nature communications 20230321 1

Schwannomas are common sporadic tumors and hallmarks of familial neurofibromatosis type 2 (NF2) that develop predominantly on cranial and spinal nerves. 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 successful treatment. How heterogeneity develops in NF2-mutant schwannomas is unknown. We have found ...[more]

PMID: 36944680

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Project description:To compare 1D (linear) tumor volume calculations and classification systems with 3D-segmented volumetric analysis (SVA), focusing specifically on their effectiveness in the evaluation and management of NF2-associated vestibular schwannomas (VS). VS were clinically followed every 6 months with cranial, thin-sliced (< 3 mm) MRI. We retrospectively reviewed and used T1-weighted post-contrast enhanced (gadolinium) images for both SVA and linear measurements. 3D-SVA was performed manually or combined with semiautomated segmentation by using axial planes. The maximum linear dimensions (MLD) were determined in three dimensions (anteroposterior, transverse, and craniocaudal planes) using axial and coronal planes. The MLD was cubed (MLD3), and orthogonal analysis (OA) was derived to establish comparability with the SVA. The Hannover and Koos classification was used to depict the size ratio in each MRI and tumor. A linear regression model was performed to compare 1D/classification systems to SVA, and the percentage deviation change of MLD3 and OA to SVA was established using a one-way multivariate variance analysis. 2586 SVA and 10344 linear measurements were performed in a cohort of 149 NF2 patients and 292 associated VS. All measurement techniques (MLD3, OA, KOOS, and Hannover) significantly (and strongly, r2 > 0.5) correlated with SVA (p < 0.001). The OA showed an even stronger positive correlation than the MLD3 to SVA. Smaller classified tumors (T1/T2, K1/K2) exhibited a low-moderate positive correlation (r2 = 0.23-0.44) compared to medium-sized (T3, K2/3) and large tumors (T4, K4; r2 = 0.54-0.76). Pre- and postoperative MLD3 and OA statistically significantly predict SVA (p < 0.001), but the postoperative correlation was weaker, particularly for MLD3 to SVA values. All analyses showed a large scatter range. In the percentage deviation analysis of MLD3 and OA from SVA, small tumors (K1/K2, T1/T2) were overestimated. Compared to the SVA, the MLD3 and especially the OA are a time-saving alternative for monitoring the tumor volume of NF2-associated VS. However, the scatter range in small/surgically reduced tumors is enormous. For this reason, they are not recommended for monitoring off-label therapy with Bevacizumab or for treatment decisions depending on a precise assessment of tumor volume and growth. Developing deep learning-based volume determinations in the future is essential to reduce SVA's time intensity.

Project description:Bilateral vestibular schwannoma is the hallmark of NF2-related schwannomatosis, a rare tumour predisposition syndrome associated with a lifetime of surgical interventions, radiotherapy and off-label use of the anti-angiogenic drug bevacizumab. Unilateral vestibular schwannoma develops sporadically in non-NF2-related schwannomatosis patients for which there are no drug treatment options available. Tumour-infiltrating immune cells such as macrophages and T-cells correlate with increased vestibular schwannoma growth, which is suggested to be similar in sporadic and NF2-related schwannomatosis tumours. However, differences between NF2-related schwannomatosis and the more common sporadic disease include NF2-related schwannomatosis patients presenting an increased number of tumours, multiple tumour types and younger age at diagnosis. A comparison of the tumour microenvironment in sporadic and NF2-related schwannomatosis tumours is therefore required to underpin the development of immunotherapeutic targets, identify the possibility of extrapolating ex vivo data from sporadic vestibular schwannoma to NF2-related schwannomatosis and help inform clinical trial design with the feasibility of co-recruiting sporadic and NF2-related schwannomatosis patients. This study drew together bulk transcriptomic data from three published Affymetrix microarray datasets to compare the gene expression profiles of sporadic and NF2-related schwannomatosis vestibular schwannoma and subsequently deconvolved to predict the abundances of distinct tumour immune microenvironment populations. Data were validated using quantitative PCR and Hyperion imaging mass cytometry. Comparative bioinformatic analyses revealed close similarities in NF2-related schwannomatosis and sporadic vestibular schwannoma tumours across the three datasets. Significant inflammatory markers and signalling pathways were closely matched in NF2-related schwannomatosis and sporadic vestibular schwannoma, relating to the proliferation of macrophages, angiogenesis and inflammation. Bulk transcriptomic and imaging mass cytometry data identified macrophages as the most abundant immune population in vestibular schwannoma, comprising one-third of the cell mass in both NF2-related schwannomatosis and sporadic tumours. Importantly, there were no robust significant differences in signalling pathways, gene expression, cell type abundance or imaging mass cytometry staining between NF2-related schwannomatosis and sporadic vestibular schwannoma. These data indicate strong similarities in the tumour immune microenvironment of NF2-related schwannomatosis and sporadic vestibular schwannoma.

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Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.

Publications

Cellular mechanisms of heterogeneity in NF2-mutant schwannoma.

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