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Proteomics-based approach reveals the involvement of spliceosomal components SF3B and SerpinB9 in dermatofibrosarcoma
Yang Xie1,2, Haifeng Li3, Tian Liu1,4
1Department of Dermatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Background:
Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous soft tissue sarcoma which is prone to high recurrence rate, and the fibrosarcomatous transformation of DFSP (FS-DFSP) is associated with a poorer prognosis and significant metastatic potential. Although the translocation of regions of chromosomes 17 and 22 that results in COL1A1-PDGFB fusion is generally acknowledged as a key genetic feature of DFSP, there is no established salvage treatment following resistance to imatinib, which targets the PDGFB pathway. In this study, we performed quantitative proteomics analyses of DFSP tumor tissues and paired adjacent normal skin, to uncover novel molecular mechanisms and potential therapeutic targets. Findings were validated using immunohistochemistry, Western Blot, Real-Time Quantitative PCR and cell viability assay.
Results:
Pathway enrichment analysis including KEGG and GSEA revealed that spliceosome pathways and ECM-receptor interaction were associated with DFSP pathogenesis. The spliceosomal components SF3B, and SerpinB9, which is the endogenous inhibitor of granzyme B, were validated to be upregulated in tumor tissues. SerpinB9 was significantly overexpressed in the FS-DFSP subtype compared with the classic-type DFSP. Treatment with the SF3B1 inhibitor, Pladienolide-B, significantly reduced tumor cell viability. siRNA-mediated knockdown of SF3B1 and SF3B2, as well as Pladienolide-B treatment, inhibited SERPINB9 expression without affecting pre-SERPINB9 mRNA levels, suggesting splicing-dependent regulation. Additionally, quantitation of the tumor microenvironment cells using the MCP-counter algorithm indicated NK cells activation. The CD56 (NK cell surface marker), biomarkers of tumor-associated macrophage (TAM) such as CD14 and CD163, and transforming growth factor-β induced (TGFBI) which is associated with TAM infiltration stained positive in DFSP tumors. SERPINB9 mRNA expression showed a positive correlation with both NK cell abundance and FCGR3A (NK cell marker) mRNA level.
Conclusions:
SerpinB9 overexpression is associated with fibrosarcomatous features in DFSP and may represent a candidate prognosis biomarker. The SF3B/SERPINB9 axis is a potential therapeutic vulnerability, particularly in FS-DFSP. NK cell- and macrophage-related signatures were evident in DFSP tumor microenvironment, warranting further functional studies.
