An integrated approach identifies mediators of local recurrence in head and neck squamous carcinoma

Francesca Citron, Joshua Armenia, Giovanni Franchin, Jerry Polesel, Renato Talamini, Sara D'Andrea, Sandro Sulfaro, Carlo M. Croce, William Klement, David Otasek, Chiara Pastrello, Tomas Tokar, Igor Jurisica, Deborah French, Riccardo Bomben, Emanuela Vaccher, Diego Serraino, Barbara Belletti, Andrea Vecchione, Luigi BarzanGustavo Baldassarre

Research output: Contribution to journalArticle

Abstract

Purpose: Head and neck squamous cell carcinomas (HNSCCs) cause more than 300,000 deaths worldwide each year. Locore-gional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients' overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected miRNAs could be used as biomarkers of recurrence in HNSCC. Experimental Design: A NanoString array was used to identify miRNAs associated with locoregional recurrence in 44 patients with HNSCC. Bioinformatic approaches validated the signature and identified potential miRNA targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results. Results: Our data identified a four-miRNA signature that classified HNSCC patients at high- or low-risk of recurrence. These miRNAs collectively impinge on the epithelial–mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, whereas miR-1, miR-133, and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-gene signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence. Conclusions: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development.

Original languageEnglish
Pages (from-to)3769-3780
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
Publication statusPublished - Jul 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Citron, F., Armenia, J., Franchin, G., Polesel, J., Talamini, R., D'Andrea, S., Sulfaro, S., Croce, C. M., Klement, W., Otasek, D., Pastrello, C., Tokar, T., Jurisica, I., French, D., Bomben, R., Vaccher, E., Serraino, D., Belletti, B., Vecchione, A., ... Baldassarre, G. (2017). An integrated approach identifies mediators of local recurrence in head and neck squamous carcinoma. Clinical Cancer Research, 23(14), 3769-3780. https://doi.org/10.1158/1078-0432.CCR-16-2814