NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
- Genentech Inc, United States
Abstract
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data file has been provided for Figure 4.
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Author details
Funding
The authors declare that there was no funding for this work
Reviewing Editor
- William C Hahn, Dana-Farber Cancer Institue, United States
Ethics
Animal experimentation: All animal studies were approved by the Institutional Animal Care and Use Committee (IACUC) at Genentech. The animal studies included herein were performed based on approved IACUC protocol numbers (LASAR 10-2319A, 16-1304, 16-1304A, 16-0098, 16-1120, 16-1143 and 16-2005, 16-1120).
Version history
- Received: March 4, 2019
- Accepted: May 28, 2019
- Accepted Manuscript published: May 30, 2019 (version 1)
- Version of Record published: July 2, 2019 (version 2)
Copyright
© 2019, Hegde et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma
eLife 8:e46551.
https://doi.org/10.7554/eLife.46551
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