{"doi":"10.1093/bjd/ljae295","title":"Chondroitin sulfate proteoglycan 4 increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying transforming growth factor-β signalling","abstract":"BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin-blistering disorder that often progresses to metastatic cutaneous squamous cell carcinoma (cSCC) at chronic wound sites. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell-surface proteoglycan that is an oncoantigen in multiple malignancies, where it modulates oncogenic signalling, drives epithelial-to-mesenchymal transition (EMT) and enables cell motility. OBJECTIVES: To evaluate CSPG4 expression and function in RDEB cSCC. METHODS: RDEB cSCC cell lines were used to assess CSPG4-dependent changes in invasive potential, transforming growth factor (TGF)-β1-stimulated signal activation and clinically relevant cytopathology metrics in an in vitro full-thickness tumour model. CSPG4 expression in RDEB cSCC and non-RDEB cSCC tumours was analysed via immunohistochemistry and single-cell RNA sequencing (scRNA-Seq), respectively. RESULTS: Inhibiting CSPG4 expression reduced invasive potential in multiple RDEB cSCC cell lines and altered membrane-proximal TGF-β signal activation via changes in SMAD3 phosphorylation. CSPG4 expression was uniformly localized to basal layer keratinocytes in fibrotic RDEB skin and tumour cells at the tumour-stroma interface at the invasive front in RDEB cSCC tumours in vivo. Analysis of published scRNA-Seq data revealed that CSPG4 expression was correlated with an enhanced EMT transcriptomic signature in cells at the tumour-stroma interface of non-RDEB cSCC tumours. Cytopathological metrics, for example nucleus : cell area ratio, were influenced by CSPG4 expression in in vitro tumour models. CONCLUSIONS: We determined that CSPG4 expression in RDEB cSCC cell lines enhanced the invasive potential of tumours. Mechanistically, CSPG4 was found to enhance membrane-proximal TGF-β-stimulated signalling via SMAD3, which is a key mediator of EMT in RDEB cSCC. The implication of these studies is that CSPG4 may represent a therapeutic target that can be leveraged for the clinical management of patients with RDEB cSCC.","journal":"British Journal of Dermatology","year":2024,"id":445081,"datarank":0.33159010023434193,"base_score":2.0794415416798357,"endowment":2.0794415416798357,"self_citation_contribution":0.31191623125197543,"citation_network_contribution":0.019673868982366484,"self_endowment_contribution":0.31191623125197543,"citer_contribution":0.019673868982366484,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":6,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9642,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":530751,"name":"Jianbo Yang","orcid":"0000-0002-1368-5294","position":1,"is_corresponding":false},{"id":36873,"name":"Matt A. Price","orcid":"0000-0002-2918-1373","position":2,"is_corresponding":false},{"id":412074,"name":"Colleen L. Forster","orcid":"0000-0001-5593-882X","position":3,"is_corresponding":false},{"id":886264,"name":"Megan Riddle","orcid":"0000-0002-9557-217X","position":4,"is_corresponding":false},{"id":545875,"name":"Christen L. Ebens","orcid":"0000-0003-2430-911X","position":5,"is_corresponding":false},{"id":20925,"name":"Frank W. Albert","orcid":"0000-0002-1380-8063","position":6,"is_corresponding":false},{"id":426678,"name":"Alessio Giubellino","orcid":"0000-0002-5352-0662","position":7,"is_corresponding":false},{"id":267855,"name":"Sarah A. Munro","orcid":"0000-0002-7233-0047","position":8,"is_corresponding":false},{"id":430835,"name":"Jakub Tolar","orcid":"0000-0002-0957-4380","position":9,"is_corresponding":false},{"id":1261492,"name":"A. Macaulay","orcid":null,"position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:01:42.089235Z","pmid":"39018437","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}