Chondroitin sulfate proteoglycan 4 (CSPG4) increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying TGFβ signaling

Allison R K Macaulay; Jianbo Yang; Matthew A Price; Colleen L Forster; Megan J Riddle; Christen L Ebens; Frank W Albert; Alessio Giubellino; James B McCarthy; Jakub Tolar

doi:10.1093/bjd/ljae295

Chondroitin sulfate proteoglycan 4 (CSPG4) increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying TGFβ signaling

Br J Dermatol. 2024 Jul 17:ljae295. doi: 10.1093/bjd/ljae295. Online ahead of print.

Authors

Allison R K Macaulay^{1

2}, Jianbo Yang³, Matthew A Price^{4

5}, Colleen L Forster⁶, Megan J Riddle¹, Christen L Ebens¹, Frank W Albert², Alessio Giubellino^{4

5}, James B McCarthy^{4

5}, Jakub Tolar¹

Affiliations

¹ Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics, Medical School, University of Minnesota, MN, USA.
² Department of Genetics, Cell Biology, & Genetics, University of Minnesota, MN, USA.
³ The Cancer Center, Union Hospital, Fujian Medical University, Fuzhou, China.
⁴ Masonic Cancer Center, University of Minnesota, MN, USA.
⁵ Department of Laboratory Medicine & Pathology, University of Minnesota, MN, USA.
⁶ Biorepository and Laboratory Services, Clinical and Translational Science Institute, University of Minnesota, MN, USA.

PMID: 39018437
DOI: 10.1093/bjd/ljae295

Abstract

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin-blistering disorder often progressing 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 signaling, 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, TGFβ1-stimulated signal activation, and clinically relevant cytopathology metrics in an in vitro full-thickness tumor model. CSPG4 expression in RDEB-cSCC and non-RDEB cSCC tumors was analyzed 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 TGFβ signal activation through changes in SMAD3 phosphorylation. CSPG4 expression was uniformly localized to basal-layer keratinocytes in fibrotic RDEB skin and tumor cells at the tumor/stroma interface at the invasive front in RDEB-cSCC tumors in vivo. Analysis of published scRNA-seq data revealed that CSPG4 expression was correlated with an enhanced EMT transcriptomic signature in cells at the tumor/stroma interface of non-RDEB cSCC tumors. Cytopathological metrics, like nucleus:cell area ratio, were influenced by CSPG4 expression in in vitro tumor models.

Conclusions: We determined that CSPG4 expression in RDEB-cSCC cell lines enhanced invasive potential. Mechanistically, CSPG4 was found to enhance membrane-proximal TGFβ-stimulated signaling through 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 clinical management in patients with RDEB-cSCC.

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