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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2019
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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 |
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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 |
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