NRG1 Is a Critical Regulator of Differentiation in TP63-driven Squamous Cell Carcinoma

Elife. 2019 May 30;8:e46551. doi: 10.7554/eLife.46551.

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.

Keywords: ERBB3; NRG1; TP63; cancer biology; human; mouse; squamous cell cancer.

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology*
  • Cell Differentiation*
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice, Nude
  • Neuregulin-1 / metabolism*
  • Receptor, ErbB-3 / metabolism
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Neuregulin-1
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • ERBB3 protein, human
  • Receptor, ErbB-3

Grant support

The authors declare that there was no funding for this work