Defects in the fanconi anemia pathway in head and neck cancer cells stimulate tumor cell invasion through DNA-PK and Rac1 signaling

Lindsey E. Romick-Rosendale, Elizabeth E. Hoskins, Lisa M. Privette Vinnedge, Grant D. Foglesong, Marion G. Brusadelli, S. Steven Potter, Kakajan Komurov, Samantha A. Brugmann, Paul F. Lambert, Randall J. Kimple, Elizabeth L. Virts, Helmut Hanenberg, Maura L. Gillison, Susanne I. Wells

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Purpose: Head and neck squamous cell carcinoma (HNSCC) remains a devastating disease, and Fanconi anemia (FA) gene mutations and transcriptional repression are common. Invasive tumor behavior is associated with poor outcome, but relevant pathways triggering invasion are poorly understood. There is a significant need to improve our understanding of genetic pathways and molecular mechanisms driving advanced tumor phenotypes, to develop tailored therapies. Here we sought to investigate the phenotypic and molecular consequences of FA pathway loss in HNSCC cells. Experimental Design: Using sporadic HNSCC cell lines with and without FA gene knockdown, we sought to characterize the phenotypic and molecular consequences of FA deficiency. FA pathway inactivation was confirmed by the detection of classic hallmarks of FA following exposure to DNA cross-linkers. Cells were subjected to RNA sequencing with qRT-PCR validation, followed by cellular adhesion and invasion assays in the presence and absence of DNA-dependent protein kinase (DNA-PK) and Rac1 inhibitors. Results: We demonstrate that FA loss in HNSCC cells leads to cytoskeletal reorganization and invasive tumor cell behavior in the absence of proliferative gains. We further demonstrate that cellular invasion following FA loss is mediated, at least in part, through NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. Conclusions: These findings demonstrate that FA loss stimulates HNSCC cell motility and invasion, and implicate a targetable DNA-PK/Rac1 signaling axis in advanced tumor phenotypes.

Original languageEnglish (US)
Pages (from-to)2062-2073
Number of pages12
JournalClinical Cancer Research
Volume22
Issue number8
DOIs
StatePublished - Apr 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Defects in the fanconi anemia pathway in head and neck cancer cells stimulate tumor cell invasion through DNA-PK and Rac1 signaling'. Together they form a unique fingerprint.

  • Cite this

    Romick-Rosendale, L. E., Hoskins, E. E., Privette Vinnedge, L. M., Foglesong, G. D., Brusadelli, M. G., Potter, S. S., Komurov, K., Brugmann, S. A., Lambert, P. F., Kimple, R. J., Virts, E. L., Hanenberg, H., Gillison, M. L., & Wells, S. I. (2016). Defects in the fanconi anemia pathway in head and neck cancer cells stimulate tumor cell invasion through DNA-PK and Rac1 signaling. Clinical Cancer Research, 22(8), 2062-2073. https://doi.org/10.1158/1078-0432.CCR-15-2209