Role of transforming growth factor-β1 in recessive dystrophic epidermolysis bullosa squamous cell carcinoma

Kirk R Twaroski; Weili Chen; Michael Pickett-Leonard; Jakub Tolar

doi:10.1111/exd.14304

Role of transforming growth factor-β1 in recessive dystrophic epidermolysis bullosa squamous cell carcinoma

Kirk R Twaroski, Weili Chen, Michael Pickett-Leonard, Jakub Tolar

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Squamous cell carcinoma (SCC) develops in more than 80% of individuals with the skin blistering disorder recessive dystrophic epidermolysis bullosa (RDEB). In contrast with UV-induced SCC, RDEB-SCC results from skin damage and has a high proliferative and metastatic rate with 5-year survival near zero. Our objective is to determine the mechanisms underlying the increased metastatic tendencies of RDEB-SCC. RDEB-SCC cultured cell lines were treated with RDEB and non-RDEB fibroblast conditioned media and assayed for migration and invasion with and without small molecule inhibitors for TGFβ and other downstream signal transduction pathways. TGFβ1 secreted by RDEB dermal fibroblasts has been found to induce migration and invasion and to increase expression of epithelial-to-mesenchymal transition markers in an RDEB-SCC line. These effects were reversed upon inhibition of TGFβ signalling and its downstream pathways MEK/ERK, P38 kinase and SMAD3. A number of small molecule inhibitors for these pathways are in different phases of various clinical trials and may be applicable to RDEB-SCC patients. Studying the mechanisms of the extreme form RDEB-SCC may inform studies of other types of SCC, as well as lead to better therapies for RDEB patients.

Original language	English (US)
Pages (from-to)	664-675
Number of pages	12
Journal	Experimental Dermatology
Volume	30
Issue number	5
DOIs	https://doi.org/10.1111/exd.14304
State	Published - May 2021

Bibliographical note

Funding Information:
This research was supported by funding from the Richard M. Schulze Family Foundation (Schulze Regenerative Skin Research Fund) and the Zona Family Fund for EB Research. The authors would like to thank Dr. Andrew South (Thomas Jefferson University in Philadelphia) for his generous gift of RDEB‐SCC cell lines.

Publisher Copyright:
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Keywords

SMAD3 inhibitors
TGFβ signalling
cell signal cascades
dermal fibroblasts
epithelial-to-mesenchymal transition

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/exd.14304

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title = "Role of transforming growth factor-β1 in recessive dystrophic epidermolysis bullosa squamous cell carcinoma",

abstract = "Squamous cell carcinoma (SCC) develops in more than 80% of individuals with the skin blistering disorder recessive dystrophic epidermolysis bullosa (RDEB). In contrast with UV-induced SCC, RDEB-SCC results from skin damage and has a high proliferative and metastatic rate with 5-year survival near zero. Our objective is to determine the mechanisms underlying the increased metastatic tendencies of RDEB-SCC. RDEB-SCC cultured cell lines were treated with RDEB and non-RDEB fibroblast conditioned media and assayed for migration and invasion with and without small molecule inhibitors for TGFβ and other downstream signal transduction pathways. TGFβ1 secreted by RDEB dermal fibroblasts has been found to induce migration and invasion and to increase expression of epithelial-to-mesenchymal transition markers in an RDEB-SCC line. These effects were reversed upon inhibition of TGFβ signalling and its downstream pathways MEK/ERK, P38 kinase and SMAD3. A number of small molecule inhibitors for these pathways are in different phases of various clinical trials and may be applicable to RDEB-SCC patients. Studying the mechanisms of the extreme form RDEB-SCC may inform studies of other types of SCC, as well as lead to better therapies for RDEB patients.",

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Role of transforming growth factor-β1 in recessive dystrophic epidermolysis bullosa squamous cell carcinoma

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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