Cargando…

NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma

Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it’s downstream effectors. In this study we demonstrate that TP63 directly regulates NRG...

Descripción completa

Detalles Bibliográficos
Autores principales: Hegde, Ganapati V, de la Cruz, Cecile, Giltnane, Jennifer M, Crocker, Lisa, Venkatanarayan, Avinashnarayan, Schaefer, Gabriele, Dunlap, Debra, Hoeck, Joerg D, Piskol, Robert, Gnad, Florian, Modrusan, Zora, de Sauvage, Frederic J, Siebel, Christian W, Jackson, Erica L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606022/
https://www.ncbi.nlm.nih.gov/pubmed/31144617
http://dx.doi.org/10.7554/eLife.46551
_version_ 1783431847723663360
author Hegde, Ganapati V
de la Cruz, Cecile
Giltnane, Jennifer M
Crocker, Lisa
Venkatanarayan, Avinashnarayan
Schaefer, Gabriele
Dunlap, Debra
Hoeck, Joerg D
Piskol, Robert
Gnad, Florian
Modrusan, Zora
de Sauvage, Frederic J
Siebel, Christian W
Jackson, Erica L
author_facet Hegde, Ganapati V
de la Cruz, Cecile
Giltnane, Jennifer M
Crocker, Lisa
Venkatanarayan, Avinashnarayan
Schaefer, Gabriele
Dunlap, Debra
Hoeck, Joerg D
Piskol, Robert
Gnad, Florian
Modrusan, Zora
de Sauvage, Frederic J
Siebel, Christian W
Jackson, Erica L
author_sort Hegde, Ganapati V
collection PubMed
description Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it’s downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin.
format Online
Article
Text
id pubmed-6606022
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-66060222019-07-03 NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma Hegde, Ganapati V de la Cruz, Cecile Giltnane, Jennifer M Crocker, Lisa Venkatanarayan, Avinashnarayan Schaefer, Gabriele Dunlap, Debra Hoeck, Joerg D Piskol, Robert Gnad, Florian Modrusan, Zora de Sauvage, Frederic J Siebel, Christian W Jackson, Erica L eLife Cancer Biology Squamous cell carcinomas (SCCs) account for the majority of cancer mortalities. Although TP63 is an established lineage-survival oncogene in SCCs, therapeutic strategies have not been developed to target TP63 or it’s downstream effectors. In this study we demonstrate that TP63 directly regulates NRG1 expression in human SCC cell lines and that NRG1 is a critical component of the TP63 transcriptional program. Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth. Together, our findings identify a lineage-specific function of NRG1 in SCCs of diverse anatomic origin. eLife Sciences Publications, Ltd 2019-05-30 /pmc/articles/PMC6606022/ /pubmed/31144617 http://dx.doi.org/10.7554/eLife.46551 Text en © 2019, Hegde et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Hegde, Ganapati V
de la Cruz, Cecile
Giltnane, Jennifer M
Crocker, Lisa
Venkatanarayan, Avinashnarayan
Schaefer, Gabriele
Dunlap, Debra
Hoeck, Joerg D
Piskol, Robert
Gnad, Florian
Modrusan, Zora
de Sauvage, Frederic J
Siebel, Christian W
Jackson, Erica L
NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
title NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
title_full NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
title_fullStr NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
title_full_unstemmed NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
title_short NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
title_sort nrg1 is a critical regulator of differentiation in tp63-driven squamous cell carcinoma
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606022/
https://www.ncbi.nlm.nih.gov/pubmed/31144617
http://dx.doi.org/10.7554/eLife.46551
work_keys_str_mv AT hegdeganapativ nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT delacruzcecile nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT giltnanejenniferm nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT crockerlisa nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT venkatanarayanavinashnarayan nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT schaefergabriele nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT dunlapdebra nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT hoeckjoergd nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT piskolrobert nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT gnadflorian nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT modrusanzora nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT desauvagefredericj nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT siebelchristianw nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma
AT jacksonerical nrg1isacriticalregulatorofdifferentiationintp63drivensquamouscellcarcinoma