Proteomic analysis of pleomorphic dermal sarcoma reveals a fibroblastic cell of origin and distinct immune evasion mechanisms

• Published in: Scientific reports 2024-05, Vol.14 (1), p.12516-12, Article 12516
• Main Authors: Klein, Sebastian, Tolkach, Yuri, Reinhardt, Hans Christian, Buettner, Reinhard, Quaas, Alexander, Helbig, Doris
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1798; 631/67/1813; 631/67/1857; Aged; AKT protein; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cutaneous sarcoma; DNA sequencing; Female; Fibroblastic differentiation; Fibroblasts - metabolism; Humanities and Social Sciences; Humans; Immune escape mechanisms; Immune Evasion; Immunosuppression; Male; Mass spectrometry; Mass spectroscopy; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Melanoma, Cutaneous Malignant; Microtubule-associated protein 1; Middle Aged; multidisciplinary; PDS; Pleomorphic dermal sarcoma; Protein profiling; Proteins; Proteomics; Proteomics - methods; Sarcoma; Sarcoma - immunology; Sarcoma - metabolism; Sarcoma - pathology; Science; Science (multidisciplinary); Signal Transduction; Skin; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Squamous cell carcinoma; Ultraviolet radiation; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-62927-x

Pleomorphic dermal sarcomas are infrequent neoplastic skin tumors, manifesting in regions of the skin exposed to ultraviolet radiation. Diagnosing the entity can be challenging and therapeutic options are limited. We analyzed 20 samples of normal healthy skin tissue (SNT), 27 malignant melanomas (MM), 20 cutaneous squamous cell carcinomas (cSCC), and 24 pleomorphic dermal sarcomas (PDS) using mass spectrometry. We explored a potential cell of origin in PDS and validated our findings using publicly available single-cell sequencing data. By correlating tumor purity (TP), inferred by both RNA- and DNA-sequencing, to protein abundance, we found that fibroblasts shared most of the proteins correlating to TP. This observation could also be made using publicly available SNT single cell sequencing data. Moreover, we studied relevant pathways of receptor/ligand (R/L) interactions. Analysis of R/L interactions revealed distinct pathways in cSCC, MM and PDS, with a prominent role of PDGFRB-PDGFD R/L interactions and upregulation of PI3K/AKT signaling pathway. By studying differentially expressed proteins between cSCC and PDS, markers such as MAP1B could differentiate between these two entities. To this end, we studied proteins associated with immunosuppression in PDS, uncovering that immunologically cold PDS cases shared a “negative regulation of interferon-gamma signaling” according to overrepresentation analysis.