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Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop

Oncogene volume 32, pages 4766–4777 (2013)Cite this article

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Abstract

Head and neck squamous cell carcinoma (HNSCC) has a proclivity for locoregional invasion. HNSCC mediates invasion in part through invadopodia-based proteolysis of the extracellular matrix (ECM). Activation of Src, Erk1/2, Abl and Arg downstream of epidermal growth factor receptor (EGFR) modulates invadopodia activity through phosphorylation of the actin regulatory protein cortactin. In MDA-MB-231 breast cancer cells, Abl and Arg function downstream of Src to phosphorylate cortactin, promoting invadopodia ECM degradation activity and thus assigning a pro-invasive role for Ableson kinases. We report that Abl kinases have an opposite, negative regulatory role in HNSCC where they suppress invadopodia and tumor invasion. Impairment of Abl expression or Abl kinase activity with imatinib mesylate enhanced HNSCC matrix degradation and 3D collagen invasion, functions that were impaired in MDA-MB-231. HNSCC lines with elevated EGFR and Src activation did not contain increased Abl or Arg kinase activity, suggesting that Src could bypass Abl/Arg to phosphorylate cortactin and promote invadopodia ECM degradation. Src-transformed Abl−/−/Arg−/− fibroblasts produced ECM degrading invadopodia containing pY421 cortactin, indicating that Abl/Arg are dispensable for invadopodia function in this system. Imatinib-treated HNSCC cells had increased EGFR, Erk1/2 and Src activation, enhancing cortactin pY421 and pS405/418 required for invadopodia function. Imatinib stimulated shedding of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) from HNSCC cells, where soluble HB-EGF enhanced invadopodia ECM degradation in HNSCC but not in MDA-MB-231. HNSCC cells treated with inhibitors of the EGFR-invadopodia pathway indicated that EGFR and Src are required for invadopodia function. Collectively, our results indicate that Abl kinases negatively regulate HNSCC invasive processes through suppression of an HB-EGF autocrine loop responsible for activating a EGFR-Src-cortactin cascade, in contrast to the invasion promoting functions of Abl kinases in breast and other cancer types. Our results provide mechanistic support for recent failed HNSCC clinical trials utilizing imatinib.

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Acknowledgements

We thank Bruce Mayer (University of Connecticut) for Abl constructs, Anthony Koleske (Yale University) for Abl−/−/Arg−/− fibroblasts, Silja Wessler (Paul-Ehrlich Institute) for the Abl shRNA construct, Elena Pugacheva (West Virginia University) for MDA-MB-231LN cells, Jim Bear (University of North Carolina) for pLL5.0 and advice on spheroid assay development. We thank Mark Auble and Barbara Frederick for technical assistance. Saracatinib and gefitinib were provided by AstraZeneca. This study was supported by NIH Grants R01 DE014578, P20 RR16440 (to SAW) and the West Virginia University Mary Babb Randolph Cancer Center. The West Virginia University Microscopy Imaging Facility (supported by the Mary Babb Randolph Cancer, NIH Grants P20 RR16440 and P30 RR032138/GM103488) is gratefully acknowledged.

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  1. L C Kelley

    Present address: 2Present address: Biology Department, Duke University, Durham, NC 27708, USA,

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  1. Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, USA

    K E Hayes, E L Walk, A G Ammer, L C Kelley, K H Martin & S A Weed

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Hayes, K., Walk, E., Ammer, A. et al. Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop. Oncogene 32, 4766–4777 (2013). https://doi.org/10.1038/onc.2012.513

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