TY - JOUR
T1 - Defects in the fanconi anemia pathway in head and neck cancer cells stimulate tumor cell invasion through DNA-PK and Rac1 signaling
AU - Romick-Rosendale, Lindsey E.
AU - Hoskins, Elizabeth E.
AU - Privette Vinnedge, Lisa M.
AU - Foglesong, Grant D.
AU - Brusadelli, Marion G.
AU - Potter, S. Steven
AU - Komurov, Kakajan
AU - Brugmann, Samantha A.
AU - Lambert, Paul F.
AU - Kimple, Randall J.
AU - Virts, Elizabeth L.
AU - Hanenberg, Helmut
AU - Gillison, Maura L.
AU - Wells, Susanne I.
N1 - Funding Information:
This work was supported in part by NIH award RO1 CA102357 (to S.I. Wells). H. Hanenberg is supported by the Lilly Foundation Physician/Scientist initiative. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/4/15
Y1 - 2016/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-2209
DO - 10.1158/1078-0432.CCR-15-2209
M3 - Article
C2 - 26603260
AN - SCOPUS:84966318839
SN - 1078-0432
VL - 22
SP - 2062
EP - 2073
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -