American Association for Cancer Research
Browse
10780432ccr152209-sup-155079_1_supp_3215975_nxc3g3.jpeg (861.06 kB)

Supplemental Figure 2 from Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion through DNA-PK and Rac1 Signaling

Download (861.06 kB)
figure
posted on 2023-03-31, 19:04 authored by 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

Cell attachment and migration assays for UM-SCC1 cells.

Funding

NIH

Lilly Foundation Physician/Scientist initiative

History

ARTICLE 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. Clin Cancer Res; 22(8); 2062–73. ©2015 AACR.

Usage metrics

    Clinical Cancer Research

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC