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<p>Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and a major cause of mortality in neurofibromatosis type 1 (NF-1). Distinguishing MPNSTs from benign neurofibromas remains challenging. We investigated fibroblast activation protein alpha (FAP) as a malignancy biomarker and theranostic target in peripheral nerve sheath tumors.&#xa0;Therefore, we integrated publicly available bulk transcriptomics, spatial transcriptomics, and single-cell RNA sequencing with immunohistochemistry (IHC) on independent archival samples. We further directly assessed clinical translatability using FAP-targeted PET/CT in an NF-1 patient undergoing work-up for suspected malignant transformation. Across independent bulk datasets, <i>FAP</i> was consistently up-regulated in MPNSTs compared with neurofibromas. In the TCGA sarcoma dataset, <i>FAP</i> varied by histotype but was clearly expressed in MPNSTs. Spatial transcriptomics revealed enrichment of <i>FAP</i>-high regions in MPNSTs and co-localization with tumor cell markers. Single-cell analysis showed <i>FAP</i> expression in MPNST tumor cells and cancer-associated fibroblasts, with the highest levels in neural crest-like tumor subpopulations previously linked to adverse prognosis; pseudotime analysis indicated decreasing <i>FAP</i> expression along trajectories toward Schwann cell precursor-like states linking <i>FAP</i> expression to a more primitive, dedifferentiated tumor cell state. IHC confirmed strong, predominantly tumor cell-intrinsic FAP expression in MPNSTs, with minimal staining in neurofibromas and normal tissues. Plexiform neurofibromas exhibited intermediate FAP expression. In clinical imaging, FAP-PET demonstrated higher tracer uptake in histologically proven MPNSTs than in benign lesions within the same patient, including a neurofibroma that was FDG-avid but FAP-negative, supporting added diagnostic specificity over FDG-PET/CT. In summary,&#xa0;FAP is robustly overexpressed in MPNSTs at transcript and protein levels, potentially concentrates in high-risk tumor cell states, and is detectable by targeted PET imaging. These findings identify FAP as a clinically relevant biomarker for malignancy in NF-1-associated tumors and support implementation of FAP-directed diagnostics and therapeutics in peripheral nerve sheath tumor work-up.</p>

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FAP expression as a marker of malignant transformation enabling in vivo characterization in peripheral nerve sheath tumors: a multimodal and translational study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月27日

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  • Nic G. Reitsam,
  • Alexander Gäble,
  • Lisa Siebenhüter,
  • Tina Schaller,
  • Friederike Liesche-Starnecker,
  • Eva Sipos,
  • Sebastian Dintner,
  • Christoph Walz,
  • John Babic,
  • Martin Trepel,
  • Malte Kircher,
  • Victoria E. Fincke,
  • Pascal D. Johann,
  • Bruno Märkl,
  • Constantin Lapa,
  • Johanna S. Enke

摘要

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and a major cause of mortality in neurofibromatosis type 1 (NF-1). Distinguishing MPNSTs from benign neurofibromas remains challenging. We investigated fibroblast activation protein alpha (FAP) as a malignancy biomarker and theranostic target in peripheral nerve sheath tumors. Therefore, we integrated publicly available bulk transcriptomics, spatial transcriptomics, and single-cell RNA sequencing with immunohistochemistry (IHC) on independent archival samples. We further directly assessed clinical translatability using FAP-targeted PET/CT in an NF-1 patient undergoing work-up for suspected malignant transformation. Across independent bulk datasets, FAP was consistently up-regulated in MPNSTs compared with neurofibromas. In the TCGA sarcoma dataset, FAP varied by histotype but was clearly expressed in MPNSTs. Spatial transcriptomics revealed enrichment of FAP-high regions in MPNSTs and co-localization with tumor cell markers. Single-cell analysis showed FAP expression in MPNST tumor cells and cancer-associated fibroblasts, with the highest levels in neural crest-like tumor subpopulations previously linked to adverse prognosis; pseudotime analysis indicated decreasing FAP expression along trajectories toward Schwann cell precursor-like states linking FAP expression to a more primitive, dedifferentiated tumor cell state. IHC confirmed strong, predominantly tumor cell-intrinsic FAP expression in MPNSTs, with minimal staining in neurofibromas and normal tissues. Plexiform neurofibromas exhibited intermediate FAP expression. In clinical imaging, FAP-PET demonstrated higher tracer uptake in histologically proven MPNSTs than in benign lesions within the same patient, including a neurofibroma that was FDG-avid but FAP-negative, supporting added diagnostic specificity over FDG-PET/CT. In summary, FAP is robustly overexpressed in MPNSTs at transcript and protein levels, potentially concentrates in high-risk tumor cell states, and is detectable by targeted PET imaging. These findings identify FAP as a clinically relevant biomarker for malignancy in NF-1-associated tumors and support implementation of FAP-directed diagnostics and therapeutics in peripheral nerve sheath tumor work-up.