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.
Highlights
Within the past decade, lineage addiction has emerged as a common paradigm to explain how certain tumors depend on co-opted survival and self-renewal programs that drive the normal development of the tissues from which they arise (Garraway and Sellers, 2006)
Studies of normal mammary basal cells established that TP63 can directly activate NRG1 transcription (Forster et al, 2014)
We found that NRG1 and TP63 expression significantly correlated in both esophageal and lung squamous cell carcinomas (LUSC) as determined from The Cancer Genome Atlas (TCGA) transcriptome data (Figure 1A)
Summary
Lineage addiction has emerged as a common paradigm to explain how certain tumors depend on co-opted survival and self-renewal programs that drive the normal development of the tissues from which they arise (Garraway and Sellers, 2006). To ascertain whether SCCs co-expressing NRG1 and ERBB3 are responsive to inhibition of NRG1 signaling, we screened a panel of cell lines from SCC indications including lung, esophageal and skin for growth sensitivity to an NRG1 blocking antibody (Hegde et al, 2013) in vitro.
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