Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma

Patrizia Cammareri, Aidan Rose, David F. Vincent, Jun Wang, Ai Nagano, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip J . Coates, Angela McHugh, Celine Pourreyron, Jasbani Dayal, Jonas Larsson, Simone Weidlich, Lindsay Spender, Gopal Sapkota, Karin J. Purdie, Charlotte Proby, Catherine A. Harwood, Irene LeighHans Clevers, Nick Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Claude Chelala, Andrew South, Owen J. Sansom, Gareth Inman

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Abstract

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis.
Original languageEnglish
Article number12493
Pages (from-to)1-7
Number of pages7
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 25 Aug 2016

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stem cells
Stem cells
deactivation
Squamous Cell Carcinoma
Stem Cells
cancer
mutations
Skin
deletion
Mutation
functional analysis
Functional analysis
Ablation
cells
lesions
inhibitors
ablation
mice
Epithelial Cells
Chemical activation

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Cammareri, Patrizia ; Rose, Aidan ; Vincent, David F. ; Wang, Jun ; Nagano, Ai ; Libertini, Silvana ; Ridgway, Rachel A. ; Athineos, Dimitris ; Coates, Philip J . ; McHugh, Angela ; Pourreyron, Celine ; Dayal, Jasbani ; Larsson, Jonas ; Weidlich, Simone ; Spender, Lindsay ; Sapkota, Gopal ; Purdie, Karin J. ; Proby, Charlotte ; Harwood, Catherine A. ; Leigh, Irene ; Clevers, Hans ; Barker, Nick ; Karlsson, Stefan ; Pritchard, Catrin ; Marais, Richard ; Chelala, Claude ; South, Andrew ; Sansom, Owen J. ; Inman, Gareth. / Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. In: Nature Communications. 2016 ; Vol. 7. pp. 1-7.
@article{8f112731ec3f4f5093602db800f67565,
title = "Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma",
abstract = "Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis.",
author = "Patrizia Cammareri and Aidan Rose and Vincent, {David F.} and Jun Wang and Ai Nagano and Silvana Libertini and Ridgway, {Rachel A.} and Dimitris Athineos and Coates, {Philip J .} and Angela McHugh and Celine Pourreyron and Jasbani Dayal and Jonas Larsson and Simone Weidlich and Lindsay Spender and Gopal Sapkota and Purdie, {Karin J.} and Charlotte Proby and Harwood, {Catherine A.} and Irene Leigh and Hans Clevers and Nick Barker and Stefan Karlsson and Catrin Pritchard and Richard Marais and Claude Chelala and Andrew South and Sansom, {Owen J.} and Gareth Inman",
note = "O.S. is supported by a Cancer Research UK core grant (A21139) and an ERC starting grant (311301). P.C. is supported by FP7 Health CP-IP - Large-scale integrating project grant (278568). D.F.V. is supported by ERC Starting grant (311301). A.M.R. is supported by Cancer Research UK centre grant (A12976). L.C.S. was supported by WWCR grant 11-0788. G.J.I. was supported by WWCR fellowship (03-0900). G.J.I., I.M.L., C.M.P., C.A.H., K.J.P., A.M., C.P. and A.P.S. were supported by a Cancer Research UK programme grant (A13044) and an ERC grant (250170). J.W., A.N. and C.C. were supported by a Cancer Research UK centre award to Barts Cancer Institute.",
year = "2016",
month = "8",
day = "25",
doi = "10.1038/ncomms12493",
language = "English",
volume = "7",
pages = "1--7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Cammareri, P, Rose, A, Vincent, DF, Wang, J, Nagano, A, Libertini, S, Ridgway, RA, Athineos, D, Coates, PJ, McHugh, A, Pourreyron, C, Dayal, J, Larsson, J, Weidlich, S, Spender, L, Sapkota, G, Purdie, KJ, Proby, C, Harwood, CA, Leigh, I, Clevers, H, Barker, N, Karlsson, S, Pritchard, C, Marais, R, Chelala, C, South, A, Sansom, OJ & Inman, G 2016, 'Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma', Nature Communications, vol. 7, 12493, pp. 1-7. https://doi.org/10.1038/ncomms12493

Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. / Cammareri, Patrizia; Rose, Aidan; Vincent, David F. ; Wang, Jun; Nagano, Ai; Libertini, Silvana; Ridgway, Rachel A.; Athineos, Dimitris; Coates, Philip J .; McHugh, Angela; Pourreyron, Celine; Dayal, Jasbani; Larsson, Jonas; Weidlich, Simone; Spender, Lindsay; Sapkota, Gopal; Purdie, Karin J.; Proby, Charlotte; Harwood, Catherine A.; Leigh, Irene; Clevers, Hans; Barker, Nick; Karlsson, Stefan ; Pritchard, Catrin; Marais, Richard; Chelala, Claude; South, Andrew; Sansom, Owen J. (Lead / Corresponding author); Inman, Gareth (Lead / Corresponding author).

In: Nature Communications, Vol. 7, 12493, 25.08.2016, p. 1-7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma

AU - Cammareri, Patrizia

AU - Rose, Aidan

AU - Vincent, David F.

AU - Wang, Jun

AU - Nagano, Ai

AU - Libertini, Silvana

AU - Ridgway, Rachel A.

AU - Athineos, Dimitris

AU - Coates, Philip J .

AU - McHugh, Angela

AU - Pourreyron, Celine

AU - Dayal, Jasbani

AU - Larsson, Jonas

AU - Weidlich, Simone

AU - Spender, Lindsay

AU - Sapkota, Gopal

AU - Purdie, Karin J.

AU - Proby, Charlotte

AU - Harwood, Catherine A.

AU - Leigh, Irene

AU - Clevers, Hans

AU - Barker, Nick

AU - Karlsson, Stefan

AU - Pritchard, Catrin

AU - Marais, Richard

AU - Chelala, Claude

AU - South, Andrew

AU - Sansom, Owen J.

AU - Inman, Gareth

N1 - O.S. is supported by a Cancer Research UK core grant (A21139) and an ERC starting grant (311301). P.C. is supported by FP7 Health CP-IP - Large-scale integrating project grant (278568). D.F.V. is supported by ERC Starting grant (311301). A.M.R. is supported by Cancer Research UK centre grant (A12976). L.C.S. was supported by WWCR grant 11-0788. G.J.I. was supported by WWCR fellowship (03-0900). G.J.I., I.M.L., C.M.P., C.A.H., K.J.P., A.M., C.P. and A.P.S. were supported by a Cancer Research UK programme grant (A13044) and an ERC grant (250170). J.W., A.N. and C.C. were supported by a Cancer Research UK centre award to Barts Cancer Institute.

PY - 2016/8/25

Y1 - 2016/8/25

N2 - Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis.

AB - Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis.

U2 - 10.1038/ncomms12493

DO - 10.1038/ncomms12493

M3 - Article

C2 - 27558455

VL - 7

SP - 1

EP - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 12493

ER -