Research Papers:

FGFR signaling regulates resistance of head and neck cancer stem cells to cisplatin

Sarah C. McDermott, Christie Rodriguez-Ramirez, Sean P. McDermott, Max S. Wicha and Jacques E. Nör _

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Oncotarget. 2018; 9:25148-25165. https://doi.org/10.18632/oncotarget.25358

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Sarah C. McDermott1, Christie Rodriguez-Ramirez2, Sean P. McDermott3, Max S. Wicha3 and Jacques E. Nör2,4,5

1Department of Orthodontics and Pediatric Dentistry, University of Michigan School of Dentistry, Ann Arbor, MI, USA

2Department of Cariology, Restorative Science & Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA

3Department of Internal Medicine–Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA

4Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA

5Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, MI, USA

Correspondence to:

Jacques E. Nör, email: jenor@umich.edu

Keywords: chemotherapy; microarray; chemoresistance; head and neck squamous cell carcinoma; tumor-initiating cells

Received: November 03, 2017     Accepted: April 25, 2018     Published: May 18, 2018


Patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have poor prognosis with less than 1-year median survival. Platinum-based chemotherapy remains the first-line treatment for HNSCC. The cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self renewing cell populations that constitute the bulk of the tumor. A small population of CSC exists within HNSCC that are relatively resistant to chemotherapy and clinically predicted to contribute to tumor recurrence. These head and neck CSCs (HNCSC) are identified by high cell-surface expression of CD44 and high intracellular activity of aldehyde dehydrogenase (ALDH) and termed ALDHhighCD44high. Here, we performed microarray analysis in two HNSCC cell lines (UM-SCC-1, UM-SCC-22B) to investigate molecular pathways active in untreated and cisplatin-resistant ALDHhighCD44high cells. Gene set enrichment analysis and iPathway analysis identified signaling pathways with major implications to the pathobiology of cancer (e.g. TNFα, IFN, IL6/STAT, NF-κB) that are enriched in cisplatin-resistant ALDHhighCD44high cells, when compared to control cells. FGF2 was also enriched in cisplatin-resistant ALDHhighCD44high, which was confirmed by ELISA analysis. Inhibition of FGF signaling using BGJ398, a pan-FGF receptor (FGFR) small-molecule inhibitor, decreased ALDHhighCD44high alone in UM-SCC-1 and preferentially targeted cisplatin-resistant ALDHhighCD44high cells in UM-SCC-22B. These findings suggest that FGFR signaling might play an important role in the resistance of head and neck CSC to cisplatin. Collectively, this work suggests that some head and neck cancer patients might benefit from the combination of cisplatin and a FGFR inhibitor.

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