Spatial transcriptomics elucidates trajectories associated with transformation in malignant peripheral nerve sheath tumors

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ID: 332064
2026
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Abstract
Abstract Background Tumor invasion and malignant transformation are spatiotemporally coordinated processes that shape clinical behavior, diagnostic classification, and treatment response. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors that can arise sporadically or in people with neurofibromatosis type 1 (NF-1) yet how distinct spatial niches underlie MPNST intra-tumor heterogeneity, local invasion or malignant transformation from benign precursors are not fully understood. Methods We integrate spatial analysis of 50,896 transcriptomes from 15 human MPNSTs with deep learning image analysis to define the interplay between genetic alterations, the immune microenvironment, and epigenetic cell fate regulation in MPNST invasion and transformation. Results Spatial transcriptomics reveal distinct infiltrating immune cells and immunomodulatory spatial clusters in sporadic compared to NF-1 associated MPNSTs. Local invasion is marked by spatially defined immunomodulatory and dedifferentiation programs. Analysis of two NF-1 associated MPNSTs with contiguous morphologically defined neurofibroma and MPNST components demonstrates NF-1 associated tumors identified a similar malignant transformation process associated with dynamic immune infiltration, chromosome 9p loss, and dedifferentiation concomitant with increased cell proliferation. Finally, deep learning morphology encoders were trained on spatial transcriptomic data to predict spatial transcriptomic cluster identity and chromosome 9p loss from hematoxylin and eosin stained (H&E) images although the generalizability of such encoders remains a challenge. Conclusions Our data provide a spatial framework for peripheral nerve sheath tumor transformation although the limited sample size of the present cohort will require additional validation of the proposed model.
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Authors Kanish Mirchia, Abhishek Bhattacharya, Jonas Krag Viken, Grant Eilers, Sixuan Pan, Iowis Zhu, Daniel Zhang, Ayesha Siddika, Varun Monga, Rosanna L. Wustrack, Brian Na, Iain D. Carmichael, Joanna J. Phillips, Line G Jacques, Arie Perry, Calixto-Hope G. Lucas, Melike Pekmezci, Harish N. Vasudevan
Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag251
URL
https://doi.org/10.1093/neuonc/noag251
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