Nerve growth factor (NGF)-TrkA axis in head and neck squamous cell carcinoma triggers EMT and confers resistance to the EGFR inhibitor erlotinib

Chengzhong Lin; Zhenhu Ren; Xi Yang; Rong Yang; Yiming Chen; Zheqi Liu; Zhenlin Dai; Yu Zhang; Youya He; Chunye Zhang; Xu Wang; Wei Cao; Tong Ji

doi:10.1016/j.canlet.2019.12.015

Nerve growth factor (NGF)-TrkA axis in head and neck squamous cell carcinoma triggers EMT and confers resistance to the EGFR inhibitor erlotinib

Cancer Lett. 2020 Mar 1:472:81-96. doi: 10.1016/j.canlet.2019.12.015. Epub 2019 Dec 12.

Authors

Chengzhong Lin¹, Zhenhu Ren², Xi Yang², Rong Yang², Yiming Chen², Zheqi Liu², Zhenlin Dai², Yu Zhang², Youya He², Chunye Zhang³, Xu Wang⁴, Wei Cao⁵, Tong Ji⁶

Affiliations

¹ The 2nd Dental Center, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China; National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
² National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200011, China.
³ National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
⁴ National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200011, China. Electronic address: wangx312016@sh9hospital.org.
⁵ National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200011, China. Electronic address: caowei561521@shsmu.edu.cn.
⁶ National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200011, China. Electronic address: jitong70@hotmail.com.

PMID: 31838083
DOI: 10.1016/j.canlet.2019.12.015

Abstract

Understanding the molecular mechanisms regulating tumor dissemination and therapeutic resistance is of central importance for effective cancer therapies. Here, we report that nerve growth factor (NGF) and its receptor TrkA facilitate epithelial-mesenchymal transition (EMT) and EGFR inhibitor resistance via STAT3 activation in head and neck squamous cell carcinoma (HNSCC). Both NGF and TrkA expression were elevated in HNSCC, indicating poor clinical outcomes. NGF was highly expressed in cancer cells and nerves in perineural niche, whereas TrkA expression was higher in cancer cells with perineural invasion. The NGF/TrkA axis could promote HNSCC cell dissemination and trigger EMT via STAT3 activation. Moreover, we discovered that the NGF/TrkA axis conferred resistance to the EGFR inhibitor erlotinib via EMT processes in HNSCC cells. Blocking TrkA signaling markedly reversed EMT and sensitized HNSCC cells to erlotinib in both in vitro and in vivo models. Overall, our results demonstrate novel evidence that the paracrine NGF/TrkA axis favors EMT and confers EGFR-targeted therapeutic resistance in HNSCC.

Keywords: EGFR; EMT; HNSCC; Perineural invasion; TrkA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Epithelial-Mesenchymal Transition / drug effects
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
Erlotinib Hydrochloride / adverse effects
Erlotinib Hydrochloride / pharmacology*
Gene Expression Regulation, Neoplastic
Humans
Mice
Nerve Growth Factor / genetics*
Paracrine Communication / drug effects
Receptor, trkA / genetics*
STAT3 Transcription Factor / genetics
Signal Transduction / drug effects
Squamous Cell Carcinoma of Head and Neck / drug therapy*
Squamous Cell Carcinoma of Head and Neck / genetics
Squamous Cell Carcinoma of Head and Neck / pathology
Xenograft Model Antitumor Assays

Substances

NGF protein, human
NTRK1 protein, human
STAT3 Transcription Factor
STAT3 protein, human
Nerve Growth Factor
Erlotinib Hydrochloride
EGFR protein, human
ErbB Receptors
Receptor, trkA