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

J. H. S. Dayal; S. M. Mason; J. C. Salas-Alanis; J. A. McGrath; R. G. Taylor; J. E. Mellerio; K. Blyth; A. P. South; G. J. Inman

doi:10.1111/bjd.19421

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

J. H. S. Dayal, S. M. Mason, J. C. Salas-Alanis, J. A. McGrath, R. G. Taylor, J. E. Mellerio, K. Blyth, A. P. South, G. J. Inman (Lead / Corresponding author)

Dentistry

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Abstract

Background: 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. Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Original language	English
Pages (from-to)	697-708
Number of pages	12
Journal	British Journal of Dermatology
Volume	184
Issue number	4
Early online date	29 Jul 2020
DOIs	https://doi.org/10.1111/bjd.19421
Publication status	Published - 9 Apr 2021

Keywords

Dermatology

ASJC Scopus subject areas

Dermatology

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10.1111/bjd.19421

Author Accepted ManuscriptAccepted author manuscript, 15.5 MB

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Dayal, J. H. S., Mason, S. M., Salas-Alanis, J. C., McGrath, J. A., Taylor, R. G., Mellerio, J. E., Blyth, K., South, A. P., & Inman, G. J. (2021). Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma. British Journal of Dermatology, 184(4), 697-708. https://doi.org/10.1111/bjd.19421

@article{85e7c5fcd06b446d86d267be806a2689,

title = "Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma",

abstract = "Background: 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. Objectives: 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.Methods: 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.Results: 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.Conclusions: 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.",

keywords = "Dermatology",

author = "Dayal, {J. H. S.} and Mason, {S. M.} and Salas-Alanis, {J. C.} and McGrath, {J. A.} and Taylor, {R. G.} and Mellerio, {J. E.} and K. Blyth and South, {A. P.} and Inman, {G. J.}",

note = "Funding Information: We would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196), with particular thanks to the Biological Services Unit and Histology. We would also like to thank Professors Christina Guttmann-Gruber and Johann W. Bauer (Department of Dermatology and EB House Austria, Saltzburg) for supplying RDEB samples. Publisher Copyright: {\textcopyright} 2020 British Association of Dermatologists",

year = "2021",

month = apr,

day = "9",

doi = "10.1111/bjd.19421",

language = "English",

volume = "184",

pages = "697--708",

journal = "British Journal of Dermatology",

issn = "0007-0963",

publisher = "Wiley",

number = "4",

}

Dayal, JHS, Mason, SM, Salas-Alanis, JC, McGrath, JA, Taylor, RG, Mellerio, JE, Blyth, K, South, AP & Inman, GJ 2021, 'Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma', British Journal of Dermatology, vol. 184, no. 4, pp. 697-708. https://doi.org/10.1111/bjd.19421

TY - JOUR

T1 - Heterogeneous addiction to transforming growth factor-beta signalling in recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma

AU - Dayal, J. H. S.

AU - Mason, S. M.

AU - Salas-Alanis, J. C.

AU - McGrath, J. A.

AU - Taylor, R. G.

AU - Mellerio, J. E.

AU - Blyth, K.

AU - South, A. P.

AU - Inman, G. J.

N1 - Funding Information: We would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196), with particular thanks to the Biological Services Unit and Histology. We would also like to thank Professors Christina Guttmann-Gruber and Johann W. Bauer (Department of Dermatology and EB House Austria, Saltzburg) for supplying RDEB samples. Publisher Copyright: © 2020 British Association of Dermatologists

PY - 2021/4/9

Y1 - 2021/4/9

N2 - Background: 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. Objectives: 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.Methods: 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.Results: 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.Conclusions: 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.

AB - Background: 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. Objectives: 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.Methods: 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.Results: 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.Conclusions: 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.

KW - Dermatology

UR - http://www.scopus.com/inward/record.url?scp=85092408212&partnerID=8YFLogxK

U2 - 10.1111/bjd.19421

DO - 10.1111/bjd.19421

M3 - Article

C2 - 32726455

SN - 0007-0963

VL - 184

SP - 697

EP - 708

JO - British Journal of Dermatology

JF - British Journal of Dermatology

IS - 4

ER -

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

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