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

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

doi:10.1038/ncomms12493

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

Patrizia Cammareri, Aidan M. Rose, David F. Vincent, Jun Wang, Ai Nagano, Silvana Libertini, Rachel A. Ridgway, Dimitris Athineos, Philip J. Coates, Angela McHugh, Celine Pourreyron, Jasbani H.S. Dayal, Jonas Larsson, Simone Weidlich, Lindsay C. Spender, Gopal P. Sapkota, Karin J. Purdie, Charlotte M. Proby, Catherine A. Harwood, Irene M. LeighHans Clevers, Nick Barker, Stefan Karlsson, Catrin Pritchard, Richard Marais, Claude Chelala, Andrew P. South, Owen J. Sansom, Gareth J. 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 TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling 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 may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.

Original language	English
Article number	12493
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12493
Publication status	Published - 25 Aug 2016
Externally published	Yes

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Cammareri, P., Rose, A. M., Vincent, D. F., Wang, J., Nagano, A., Libertini, S., Ridgway, R. A., Athineos, D., Coates, P. J., McHugh, A., Pourreyron, C., Dayal, J. H. S., Larsson, J., Weidlich, S., Spender, L. C., Sapkota, G. P., Purdie, K. J., Proby, C. M., Harwood, C. A., ... Inman, G. J. (2016). Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. Nature Communications, 7, Article 12493. https://doi.org/10.1038/ncomms12493

@article{3592784737f74b56840f7ec63ee51674,

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 TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling 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 may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.",

author = "Patrizia Cammareri and Rose, {Aidan M.} 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 Dayal, {Jasbani H.S.} and Jonas Larsson and Simone Weidlich and Spender, {Lindsay C.} and Sapkota, {Gopal P.} and Purdie, {Karin J.} and Proby, {Charlotte M.} and Harwood, {Catherine A.} and Leigh, {Irene M.} and Hans Clevers and Nick Barker and Stefan Karlsson and Catrin Pritchard and Richard Marais and Claude Chelala and South, {Andrew P.} and Sansom, {Owen J.} and Inman, {Gareth J.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = aug,

day = "25",

doi = "10.1038/ncomms12493",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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

TY - JOUR

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

AU - Cammareri, Patrizia

AU - Rose, Aidan M.

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 H.S.

AU - Larsson, Jonas

AU - Weidlich, Simone

AU - Spender, Lindsay C.

AU - Sapkota, Gopal P.

AU - Purdie, Karin J.

AU - Proby, Charlotte M.

AU - Harwood, Catherine A.

AU - Leigh, Irene M.

AU - Clevers, Hans

AU - Barker, Nick

AU - Karlsson, Stefan

AU - Pritchard, Catrin

AU - Marais, Richard

AU - Chelala, Claude

AU - South, Andrew P.

AU - Sansom, Owen J.

AU - Inman, Gareth J.

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 TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling 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 may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, 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 TGFβ Smad signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through Braf V600E or Kras G12D knockin) and TGFβ signalling 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 may act as cells of origin for cSCC, and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signalling, are driving events of skin tumorigenesis.

UR - http://www.scopus.com/inward/record.url?scp=84983752553&partnerID=8YFLogxK

U2 - 10.1038/ncomms12493

DO - 10.1038/ncomms12493

M3 - Article

C2 - 27558455

AN - SCOPUS:84983752553

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12493

ER -

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

Abstract

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