Applied Functional Genomics

Soft-tissue sarcoma with FUS-TFCP2 or EWSR1-TFCP2 fusions

Rhabdomyosarcoma (RMS) is a soft tissue sarcoma subtype consisting of malignant immature progenitor cells with myogenic differentiation and is thought to originate from skeletal muscle. Our collaborators of the MASTER program (Stefan Fröhling, Christoph Heilig) identified several RMS cases with FUS or EWSR1 fused to the transcription factor TFCP2. These FUS- or EWSR1-TFCP2-positive RMS were recognized in the recently updated WHO classification (2020), but their classification, pathogenesis, and optimal treatment were unclear. In an interdisciplinary effort by our group together with colleagues at DKFZ, NCT Heidelberg, KiTZ, NCT Dresden, and the Institute of Pathology in Münster, we evaluated the clinical, histopathologic, genomic, transcriptomic, and epigenomic features of these patients and studied these tumors' functional and mechanistic underpinnings. Key findings were that TFCP2-rearranged neoplasms should be classified as undifferentiated sarcoma rather than RMS, arise via stepwise sarcomagenesis, and harbor various molecular alterations that represent candidate therapeutic targets, i.e., overexpressed ALK variants, CDKN2A/MTAP co-deletions, and TFCP2 fusion-induced DNA damage repair deficiency. This study illustrates how precision oncology employing comprehensive molecular profiling enables the categorization and biological understanding of rare cancers, which can translate back into new approaches to the clinical management of these often difficult-to-treat entities. (Schöpf, Uhrig, Heilig, Lee et al., Nat Commun 15(1):51, 2024)

Myxoid liposarcoma (MLS)

MLS is a malignant tumor of adipocytic origin and is driven by the FUS-DDIT3 fusion gene, which encodes an abnormal transcription factor. By using shRNA screening, we discovered a novel requirement of YAP1 in this cancer type, and demonstrated overactive YAP1 signaling as a unifying feature of MLS development. Mechanistically, FUS-DDIT3 promotes YAP1 expression, nuclear localization, and transcriptional activity and is physically associated with YAP1 in the nucleus of MLS cells. Pharmacological inhibition of YAP1 activity impairs MLS cell growth in vitro and in vivo. Therefore, YAP1 might represent a novel target for therapeutic intervention. This project was carried out together with our long-time cooperation partners Wolfgang Hartmann (Translational Pathology, University Hospital Münster) and Stefan Fröhling (NCT Heidelberg and DKFZ). (Trautmann and Cheng et al., EMBO Molecular Medicine e9889-15, 2019)