Loss of Trop2 causes ErbB3 activation through a neuregulin-1-dependent mechanism in the mesenchymal subtype of HNSCC.

Kaihua Zhang,Loren S Michel,Matthew J Ellis,Christopher A Maher,Brian A Van Tine,James Lewis,Elana J Fertig,Andreas Herrlich,Lamont Jones,Randall J Kimple,Douglas Adkins,Christine H Chung,Sora Lim

doi:10.18632/oncotarget.2423

Abstract

In head and neck squamous cell cancer (HNSCC), four intrinsic subtypes (or groups) have been identified, and each one possesses a unique biology that will require specific treatment strategies. We previously reported that mesenchymal (group 2) tumors exhibit reduced levels of Trop2 expression. In this study, we investigated the functional role of Trop2 in HNSCC and find that loss results in autocrine activation of the EGFR family member ErbB3 via neuregulin-1. Trop2 localizes to both the cell surface and cytosol of HNSCC cells and forms a complex with neuregulin-1, which is predominantly cytosolic. Inactivation of Trop2 increases the concentration of neuregulin-1 at the cell surface where it is cleaved to activate ErbB3. In primary HNSCC, detection of ErbB3 activation was limited to Trop2 negative tumors. An analysis of the Cancer Genome Atlas (TCGA) HNSCC dataset confirms enrichment for ErbB3 activity in mesenchymal tumors. Notably, Trop2 loss triggers sensitivity to anti-ErbB3 antibodies, which results in reduced proliferation and tumorigenic growth of Trop2 negative HNSCC cancer cells. These results uncover a molecular mechanism by which tumor cells control the amount of cell-surface neuregulin-1 available for cleavage and ErbB3 activation. Moreover, we demonstrate that Trop2 is a potential surrogate biomarker to identify tumors with ErbB3 activation and may therefore respond to anti-ErbB3 therapeutics.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease whose behavior is dictated by the site of origin within the head and neck as well as the underlying etiology [1]
The relationship between low Trop2 expression and elevated ErbB3 activation was observed in primary HNSCC tumors, and importantly, we demonstrate that Trop2 loss confers sensitivity to ErbB3 antibodies in tumor xenografts derived from HNSCC cells
To investigate the relationship between Trop2 loss and signaling in HNSCC, we examined the effects of reducing Trop2 levels in head and neck squamous cancer cells

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease whose behavior is dictated by the site of origin within the head and neck as well as the underlying etiology [1] Molecular profiling of these biologically heterogeneous tumors has revealed four distinct subtypes [2]. Despite the recent www.impactjournals.com/oncotarget validation of the HNSCC subtypes, much remains to be learned concerning their biology before knowledge of the subtypes will have an impact on clinical decision-making This situation lies in stark contrast to the successful application of subtype information in other tumor types such as breast [5] and colon [6] cancer, where molecular subtyping guides the selection of targeted therapies as well as the rational development of experimental therapeutics

Methods

Results

Conclusion