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Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma.

Authors
  • Dayal, J H S1, 2
  • Mason, S M1
  • Salas-Alanis, J C3
  • McGrath, J A4
  • Taylor, R G2
  • Mellerio, J E4
  • Blyth, K1, 5
  • South, A P6
  • Inman, G J1, 2, 5
  • 1 Cancer Research UK Beatson Institute, Glasgow, UK.
  • 2 Division of Cancer Research, Ninewells Hospital and Medical School, Jacqui Wood Cancer Centre, University of Dundee, Dundee, UK.
  • 3 Department of Basic Sciences, Health Sciences Division, Universidad de Monterrey, Guadalupe, Nuevo León, México.
  • 4 St John's Institute of Dermatology, King's College London, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • 5 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 6 Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Type
Published Article
Journal
British Journal of Dermatology
Publisher
Wiley (Blackwell Publishing)
Publication Date
Apr 01, 2021
Volume
184
Issue
4
Pages
697–708
Identifiers
DOI: 10.1111/bjd.19421
PMID: 32726455
Source
Medline
Language
English
License
Unknown

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is associated with a high mortality rate due to the development of life-threatening, metastatic cutaneous squamous cell carcinoma (cSCC). Elevated transforming growth factor-beta (TGF-β) signalling is implicated in cSCC development and progression in patients with RDEB. To determine the effect of exogenous and endogenous TGF-β signalling in RDEB cSCC with a view to assessing the potential of targeting TGF-β signalling for RDEB cSCC therapy. A panel of 11 patient-derived RDEB cSCC primary tumour keratinocyte cell lines (SCCRDEBs) were tested for their signalling and proliferation responses to exogenous TGF-β. Their responses to TGF-β receptor type-1 (TGFBR1) kinase inhibitors [SB-431542 and AZ12601011 (AZA01)] were tested using in vitro proliferation, clonogenicity, migration and three-dimensional invasion assays, and in vivo tumour xenograft assays. All SCCRDEBs responded to exogenous TGF-β by activation of canonical SMAD signalling and proliferative arrest. Blocking endogenous signalling by treatment with SB-431542 and AZ12601011 significantly inhibited proliferation (seven of 11), clonogenicity (six of 11), migration (eight of 11) and invasion (six of 11) of SCCRDEBs. However, these TGFBR1 kinase inhibitors also promoted proliferation and clonogenicity in two of 11 SCCRDEB cell lines. Pretreatment of in vitro TGFBR1-addicted SCCRDEB70 cells with SB-431542 enhanced overall survival and reduced tumour volume in subcutaneous xenografts but had no effect on nonaddicted SCCRDEB2 cells in these assays. Targeting TGFBR1 kinase activity may have therapeutic benefit in the majority of RDEB cSCCs. However, the potential tumour suppressive role of TGF-β signalling in a subset of RDEB cSCCs necessitates biomarker identification to enable patient stratification before clinical intervention. © 2020 British Association of Dermatologists.

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