Academic Journal
Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma.
| العنوان: | Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma. |
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| المؤلفون: | 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., Leigh, I. M., Clevers, H., Barker, N., Karlsson, S., Pritchard, Catrin, Marais, R., Chelala, C., South, A. P., Sansom, O. J., Inman, G. J. |
| بيانات النشر: | Nature Publishing Group |
| سنة النشر: | 2016 |
| المجموعة: | University of Leicester: Leicester Research Archive (LRA) |
| الوصف: | The WES data for the 30 samples have been deposited in the European Genome-phenome Archive under accession code EGAS00001001892. The authors declare that all other relevant data supporting the findings of this study are available within the article and its Supplementary Information files. Additional information can be obtained from the corresponding authors (G.J.I. and O.J.S.). Supplementary Information accompanies this paper at http://www.nature.com/naturecommunications ; 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 signalling, which is localized to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFb signalling ablation (through Tgfbr1 deletion) in LGR5 þ 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 þ ve cells also results in cSCC development. These findings indicate that LGR5 þ 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 TGFb signalling, are driving events of skin tumorigenesis ; 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 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2041-1723 |
| Relation: | Nature Communications, 2016 7:12493; http://www.nature.com/articles/ncomms12493; http://hdl.handle.net/2381/38458 |
| DOI: | 10.1038/ncomms12493 |
| الاتاحة: | http://www.nature.com/articles/ncomms12493 http://hdl.handle.net/2381/38458 https://doi.org/10.1038/ncomms12493 |
| Rights: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.108A8338 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20411723 |
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| DOI: | 10.1038/ncomms12493 |