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

eLife

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[1] Bioinformatics, Genentech, South San Francisco, United States;Discovery Oncology, Genentech, South San Francisco, United States;Molecular Biology, Genentech, South San Francisco, United States;Molecular Oncology, Genentech, South San Francisco, United States;Pathology, Genentech, South San Francisco, United States;Translational Oncology, Genentech, South San Francisco, United States;

关键词: NRG1;    ERBB3;    TP63;    squamous cell cancer;    Human;    Mouse;   

DOI  :  10.7554/eLife.46551

来源: publisher

【 摘 要 】

10.7554/eLife.46551.001Squamous 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.

【 授权许可】

CC BY