Research Article
No access
Published Online: 3 May 2021

BRAFV600E Overrides NOTCH Signaling in Thyroid Cancer

Publication: Thyroid
Volume 31, Issue Number 5

Abstract

Background: Several mechanisms likely cooperate with the mitogen-activated protein (MAP)-kinase pathway to promote cancer progression in the thyroid. One putative pathway is NOTCH signaling, which is implicated in several other malignancies. In thyroid cancer, data regarding the role of the NOTCH pathway are insufficient and even contradictory.
Methods: A BRAFV600E-driven papillary thyroid carcinoma (PTC) mouse model was subjected to NOTCH pathway genetic alterations, and the tumor burden was followed by ultrasound. Further analyses were performed on PTC cell lines or noncancerous cells transfected with NOTCHIC or BRAFV600E, which were then subjected to pharmacological treatment with MAP-kinase or NOTCH pathway inhibitors.
Results: The presence of the BRAFV600E mutation coupled with overexpression of the NOTCH intracellular domain led to significantly bigger thyroid tumors in mice, to a more aggressive carcinoma, and decreased overall survival. Although more cystic, the tumors did not progress into anaplastic thyroid carcinomas. On the contrary, the deletion of RBP-jκ (a major cofactor involved in NOTCH signaling) did not alter the phenotype in mice. BRAFV600E-mutated PTC cell lines were resistant to pharmacological inhibition of the NOTCH pathway. Inhibition of MEK1/2 uncovered a predominant effect on Hes1/Hey1 transcription compared with NOTCH inhibition in BRAFV600E-mutated cell lines. Finally, γ-secretase activity and γ-secretase subunit transcription levels were dependent on ERK activation. Our findings suggest that MAP-kinase activity overrides the NOTCH pathway in the context of thyroid cancer.
Conclusions: The interaction between the BRAF and NOTCH pathways demonstrates that the BRAFV600E mutation might bypass NOTCH and exert a strong positive effect on NOTCH downstream targets in thyroid carcinoma.

Get full access to this article

View all available purchase options and get full access to this article.

References

1. Bray F, Ferlay J, Soerjomataram I 2018 Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424.
2. Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, Maurer MS, Mciver B, Mullan BP, Oberg AL, Powell CC, Van Heerden JA, Goellner JR 2002 Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940–1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 26:879–885.
3. Hundahl SA, Fleming ID, Fremgen AM, Menck HR 1998 A national cancer data base report on 53, 856 cases of thyroid carcinoma treated in the U. S., 1985–1995. Cancer 83:2638–2648.
4. Xing M 2005 BRAF mutation in thyroid cancer. Endocr Relat Cancer 12:245–262.
5. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA 2002 Mutations of the BRAF gene in human cancer. Nature 417:949–954.
6. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N 2009 BRAF is associated with disabled feedback inhibition of RAF–MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci U S A 106:4519–4524.
7. Charles RP, Iezza G, Amendola E, Dankort D, McMahon M 2011 Mutationally activated BRAFV600E elicits papillary thyroid cancer in the adult mouse. Cancer Res 71:3863–3871.
8. Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X 2005 Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 103:2261–2268.
9. Charles R-P, Silva J, Iezza G, Phillips WA, McMahon M 2014 Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis. Mol Cancer Res 12:979–986.
10. Artavanis-tsakonas S, Matsuno K, Fortini ME 1995 Notch signaling. Science 10193:225–232.
11. Wharton KA, Johansen KM 1985 Nucleotide sequence from the neumgenic locus notch implies a gene product that shares homology with proteins containing EGF like repeats. Cell 43:567–581.
12. Struhl G, Adachi A 2000 Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins. Mol Cell 6:625–636.
13. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-tsakonas S, Griffin JD 2000 MAML1, a human homologue of Drosophila Mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 26:484–489.
14. Hurlbut GD, Kankel MW, Lake RJ, Artavanis-Tsakonas S 2007 Crossing paths with Notch in the hyper-network. Curr Opin Cell Biol 19:166–175.
15. Poulson DF 1937 Chromosomal deficiencies and the embryonic. Proc Natl Acad Sci USA 23:133–137.
16. Lehmann R, Dietrich U 1981 Mutations of early neurogenesis in Drosophila. Wilhelm Roux Arch 190:226–229.
17. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J 1991 TAN-l, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–661.
18. Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, Brown EJ, Capobianco AJ, Herlyn M, Liu Z 2005 Activation of Notch1 signaling is required for β-catenin–mediated human primary melanoma progression. J Clin Invest 115:3166–3176.
19. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, Grunn A, Fangazio M, Capello D, Monti S, Cresta S, Gargiulo E, Forconi F, Guarini A, Arcaini L, Paulli M, Laurenti L, Larocca LM, Marasca R, Gattei V, Oscier D, Bertoni F, Mullighan CG, Foà R, Pasqualucci L, Rabadan R, Dalla-favera R 2011 Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 208:1389–1401.
20. Klinakis A, Lobry C, Abdel-wahab O, Oh P, Haeno H, Buonamici S, Van De Walle I, Cathelin S, Trimarchi T, Liu C, Ibrahim S, Beran M, Zavadil J, Efstratiadis A, Taghon T, Michor F, Levine RL, Aifantis I 2011 A novel tumor suppressor function for the Notch pathway in myeloid leukemia. Nature 473:230–233.
21. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, Van Noort M, Hui C-C, Clevers H, Dotto GP, Radtke F 2003 Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 33:416–421.
22. Geers C, Colin IM, Gerard AC, Gérard A-C 2011 Delta-like 4/Notch pathway is differentially regulated in benign and malignant thyroid tissues. Thyroid 21:1323–1330.
23. Kim HJ, Kim M, Kim A, Koh JS 2017 The role of Notch1 signaling in anaplastic thyroid carcinoma. Cancer Res Treat 49:509–517.
24. Ferretti E, Tosi E, Po A, Scipioni A, Morisi R, Espinola MS, Russo D, Durante C, Schlumberger M, Screpanti I, Filetti S, Gulino A 2008 Notch signaling is involved in expression of thyrocyte differentiation markers and is down-regulated in thyroid tumors. J Clin Endocrinol Metab 93:4080–4087.
25. Yu XM, Jaskula-Sztul R, Georgen MR, Aburjania Z, Somnay YR, Leverson G, Sippel RS, Lloyd R V., Johnson BP, Chen H 2016 Notch1 signaling regulates the aggressiveness of differentiated thyroid cancer and inhibits SERPINE1 expression. Clin Cancer Res 22:3582–3592.
26. Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M 2007 A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21:379–384.
27. Murtaugh LC, Stanger BZ, Kwan KM, Melton DA 2003 Notch singaling controls multiple steps of pancreatic differentiation. Proc Natl Acad Sci U S A 100:14920–14925.
28. Han H, Tanigaki K, Yamamoto N, Kuroda K, Yoshimoto M, Nakahata T, Ikuta K, Honjo T 2002 Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int Immunol 14:637–645.
29. Undeutsch H, Christoffer L, Offermanns S, Kero J 2014 A mouse model with tamoxifen-inducible thyrocyte-specific Cre recombinase activity. Genesis 340:333–340.
30. Roelli MA, Ruffieux-Daidié D, Stooss A, Elmokh O, Phillips WA, Dettmer MS, Charles R-P 2017 PIK3CA H1047R-induced paradoxical ERK activation results in resistance to BRAF V600E specific inhibitors in BRAF V600E PIK3CA H1047R double mutant thyroid tumors. Oncotarget 8:103207–103222.
31. Wong SH, Walker JA, Jolin HE, Drynan LF, Hams E, Camelo A, Barlow JL, Neill DR, Panova V, Koch U, Radtke F, Hardman CS, Hwang YY, Fallon PG, McKenzie ANJ 2012 Transcription factor RORα is critical for nuocyte development. Nat Immunol 13:229–236.
32. ElMokh O, Ruffieux-Daidié D, Roelli M., Stooss A, Phillips W., Gertsch J, Dettmer M., Charles R-P 2017 Combined MEK and Pi3’-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo. Oncotarget 8:24604–24620.
33. Häfliger P, Graff J, Rubin M, Stooss A, Dettmer MS, Altmann K-H, Gertsch J, Charles R-P 2018 The LAT1 inhibitor JPH203 reduces growth of thyroid carcinoma in a fully immunocompetent mouse model. J Exp Clin Cancer Res 37:234.
34. Chen W, Possemato R, Campbell KT, Plattner CA, Pallas DC, Hahn WC 2004 Identification of specific PP2A complexes involved in human cell transformation. Cancer Cell 5:127–136.
35. Brady DC, Crowe MS, Turski ML, Hobbs GA, Yao X, Chaikuad A, Knapp S, Xiao K, Campbell SL, Thiele DJ, Counter CM 2014 Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature 509:492–496.
36. Ong C-T, Cheng H-T, Chang L-W, Ohtsuka T, Kageyama R, Stormo GD, Kopan R 2006 Target selectivity of vertebrate Notch proteins. J Biol Chem 281:5106–5119.
37. Kim S-K, Park H-J, Hong HS, Baik EJ, Jung MW, Mook-Jung I 2006 ERK1/2 is an endogenous negative regulator of the γ-secretase activity. FASEB J 20:1–22.
38. Dees C, Tomcik M, Zerr P, Akhmetshina A, Horn A, Palumbo K, Beyer C, Zwerina J, Distler O, Schett G, Distler JHW 2011 Notch signalling regulates fibroblast activation and collagen release in systemic sclerosis. Ann Rheum Dis 70:1304–1310.
39. Manderfield LJ, High FA, Engelka KA, Liu F, Li L, Rentschler S, Epstein JA 2013 Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation 125:314–323.
40. Asioli S, Erickson LA, Righi A, Lloyd RV. 2013 Papillary thyroid carcinoma with hobnail features: histopathologic criteria to predict aggressive behavior. Hum Pathol 44:320–328.
41. Morris LGT, Shaha AR, Tuttle RM, Sikora AG, Ganly I 2010 Tall-cell variant of papillary thyroid carcinoma: a matched-pair analysis of survival. Thyroid 20:153–158.
42. Jung CW, Kong JS, Seol H, Park S, Koh JS, Lee S-S, Kim MJ, Choi IJ, Myung JK 2017 Expression of activated Notch1 and HEY1 in papillary thyroid carcinoma. Histopathology 70:301–308.
43. Turkoz M, Townsend RR, Kopan R 2016 The Notch intracellular domain has an RBPj-independent role during mouse hair follicular development. J Invest Dermatol 136:1106–1115.
44. Stockhausen M-T, Sjölund J, Axelson H 2005 Regulation of the Notch target gene Hes-1 by TGFα induced Ras/MAPK signaling in human neuroblastoma cells. Exp Cell Res 310:218–228.
45. Tremblay I, Paré E, Arsenault D, Douziech M, Boucher MJ 2013 The MEK/ERK pathway promotes NOTCH signalling in pancreatic cancer cells. PLoS One 8:1–11.
46. Yamashita AS, Geraldo MV, Fuziwara CS, Kulcsar MAV, Friguglietti CUM, da Costa RB, Baia GS, Kimura ET 2013 Notch pathway is activated by MAPK signaling and influences papillary thyroid cancer proliferation. Transl Oncol 6:197–205.
47. Verdile G, Gandy SE, Martins RN 2007 The role of presenilin and its interacting proteins in the biogenesis of Alzheimer's beta amyloid. Neurochem Res 32:609–623.
48. Tung YT, Hsu WM, Wang BJ, Wu SY, Yen CT, Hu MK, Liao YF 2008 Sodium selenite inhibits γ-secretase activity through activation of ERK. Neurosci Lett 440:38–43.

Information & Authors

Information

Published In

cover image Thyroid®
Thyroid
Volume 31Issue Number 5May 2021
Pages: 787 - 799
PubMed: 33012268

History

Published online: 3 May 2021
Published in print: May 2021
Published ahead of print: 12 November 2020
Published ahead of production: 3 October 2020

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Florian Traversi
Institute of Biochemistry and Molecular Medicine, and Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
Amandine Stooss
Institute of Biochemistry and Molecular Medicine, and Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.
Matthias S. Dettmer
Institute of Pathology, University of Bern, Bern, Switzerland.
Roch-Philippe Charles [email protected]
Institute of Biochemistry and Molecular Medicine, and Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bern, Switzerland.

Notes

Address correspondence to: Roch-Philippe Charles, PhD, Institute of Biochemistry and Molecular Medicine, Swiss National Center of Competence in Research (NCCR) TransCure, University of Bern, Bühlstrasse 28, Bern CH-3012, Switzerland [email protected]

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This work was supported by the Swiss National Foundation grant 31003A_149824/1. The laboratory of RPC is also supported by the Swiss National Science Foundation grant NCCR-TransCure.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top