Decoding mechanisms of malignant progression of peripheral nerve sheath tumors

• Applicant: Dr. Catena Kresbach
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558134894

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive tumors, characterized by early metastasis and a devastating prognosis. MPNST can either occur sporadically or in the context of the tumor predisposition syndrome neurofibromatosis type 1 (NF1). NF1 patients typically develop plexiform neurofibromas (PNF) - benign neoplasms of peripheral nerves that can occur throughout the entire body. PNF can progress to MPNST via an intermediate state called "atypical neuro-fibromatous lesions of unknown biological potential" (ANNUBP). So far, the exact mechanisms of malignant transformation are not sufficiently understood. On a histological level, MPNST typically display a pronounced intra-tumoral heterogeneity, comprising areas of high malignancy and such corresponding to ANNUBP or even PNF. We will study whether this intra-tumoral heterogeneity of MPNST can help to reconstruct the exact mechanisms of malignant progression. Firstly, we will perform detailed morphological and epigenetic profiling of specific PNF and ANNUBP as well as of heterogeneous areas within MPNST. Second, we will characterize tumor cell subpopulations and the tumor microenvironment by conducting single-cell transcriptome analysis of PNF, ANNUBP and of MPNST with intratumoral heterogeneity. Third, we will perform spatially resolved transcriptome analysis to investigate the spatial distribution and crosstalk between tumor cell subpopulations and tumor microenvironment during malignant progression. Based on such detailed novel insights, we seek to improve histology-based and molecular diagnostic methods that help improve clinical decision making. At the same time, we aim to identify highly specific therapeutic targets to improve treatment strategy, therapy outcome, and last but not least quality of life of patients with MPNST.

• DFG Programme: Research Grants