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Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion Through DNA-PK and Rac1 Signaling Lindsey E

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Defects in the Fanconi Anemia Pathway in Head and Neck Cancer Cells Stimulate Tumor Cell Invasion Through DNA-PK and Rac1 Signaling Lindsey E Published OnlineFirst November 24, 2015; DOI: 10.1158/1078-0432.CCR-15-2209 Biology of Human Tumors Clinical Cancer Research 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-Rosendale1, Elizabeth E. Hoskins1, Lisa M. Privette Vinnedge1, Grant D. Foglesong1, Marion G. Brusadelli1, S. Steven Potter2, Kakajan Komurov1, Samantha A. Brugmann2, Paul F. Lambert3, Randall J. Kimple4, Elizabeth L. Virts5, Helmut Hanenberg5,6,7, Maura L. Gillison8, and Susanne I. Wells1 Abstract Purpose: Head and neck squamous cell carcinoma (HNSCC) hallmarks of FA following exposure to DNA cross-linkers. Cells remains a devastating disease, and Fanconi anemia (FA) gene were subjected to RNA sequencing with qRT-PCR validation, mutations and transcriptional repression are common. Invasive followed by cellular adhesion and invasion assays in the presence tumor behavior is associated with poor outcome, but relevant and absence of DNA-dependent protein kinase (DNA-PK) and pathways triggering invasion are poorly understood. There is a Rac1 inhibitors. significant need to improve our understanding of genetic Results: We demonstrate that FA loss in HNSCC cells leads to pathways and molecular mechanisms driving advanced tumor cytoskeletal reorganization and invasive tumor cell behavior in the phenotypes, to develop tailored therapies. Here we sought to absence of proliferative gains. We further demonstrate that cellular investigate the phenotypic and molecular consequences of FA invasion following FA loss is mediated, at least in part, through pathway loss in HNSCC cells. NHEJ-associated DNA-PK and downstream Rac1 GTPase activity. Experimental Design: Using sporadic HNSCC cell lines with Conclusions: These findings demonstrate that FA loss stimu- and without FA gene knockdown, we sought to characterize the lates HNSCC cell motility and invasion, and implicate a target- phenotypic and molecular consequences of FA deficiency. FA able DNA-PK/Rac1 signaling axis in advanced tumor phenotypes. pathway inactivation was confirmed by the detection of classic Clin Cancer Res; 1–12. Ó2015 AACR. Introduction bearing poor rates of remission (1, 2). Unfortunately, decades of research have not improved HNSCC outcomes significantly, In the general population, HNSCC is associated with smoking, and the classic therapeutic option, a combination of surgery, alcohol consumption, and HPV infection, and represents the sixth radiation, and chemotherapy, leaves patients permanently dis- leading type of cancer worldwide, with an annual incidence of figured. Thus, there is a need to improve our understanding of the 500,000. More than half of sporadic HNSCCs are diagnosed at biologic processes driving local invasiveness and develop novel locally advanced or metastatic stages, and approximately 50% of approaches for the treatment of late-stage tumors. Previous exome treated patients relapse with local or distant metastasis, both þ À sequencing data demonstrated that 11% of HPV and HPV HNSCCs harbor nonsynonymous mutations in FA DNA repair 1 genes (3). In addition to classic loss-of-function mutations, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital FANCB FANCC FANCF FANCJ Medical Center, Cincinnati, Ohio. 2Division of Developmental Biology, transcriptional repression of , , , , Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3McAr- and FANCM (e.g., by promoter methylation) has been noted in dle Laboratory for Cancer Research, University of Wisconsin School of dysplastic HN tissue and HNSCC (4, 5). This suggests that loss of Medicine and Public Health, Madison, Wisconsin. 4Department of Human Oncology, University of Wisconsin School of Medicine and FA pathway function can provide a selective advantage to HNSCC Public Health, Madison,Wisconsin. 5Department of Pediatrics, Indiana cells. However, the underlying biologic mechanisms, aside from University School of Medicine, Indianapolis, Indiana. 6Department of genome instability, remain poorly understood. Otorhinolaryngology, Heinrich Heine University, Duesseldorf, Ger- many. 7Department of Pediatrics III, University Children's Hospital Major advances in understanding how defective DNA repair Essen, University of Duisburg-Essen, Essen, Germany. 8Internal Med- pathways contribute to tumorigenesis have been achieved by icine—Hematology & Oncology, Comprehensive Cancer Center, The studying DNA repair deficiency syndromes that often manifest Ohio State, University College of Medicine, Columbus, Ohio. during the first years of life (6). Fanconi anemia (FA) is a rare Note: Supplementary data for this article are available at Clinical Cancer inherited disorder where every cell of an affected individual is Research Online (http://clincancerres.aacrjournals.org/). exquisitely sensitive to DNA cross-linking agents including mito- Corresponding Author: Susanne Wells, Cancer and Blood Diseases Institute, mycin C or cisplatin (for reviews on mechanisms and disease Cincinnati Children's Hospital, 3333 Burnet Ave., MLC 7013, S7-206, Cincinnati, manifestations see (refs. 7 and 8 and references within). Clini- OH 45229. Phone: 513-636-5986; Fax: 513-636-2880; E-mail: cally, patients with FA are characterized by frequent congenital [email protected] abnormalities, early progressive bone marrow failure, and a high doi: 10.1158/1078-0432.CCR-15-2209 propensity for developing malignancies, especially acute myeloid Ó2015 American Association for Cancer Research. leukemia, and squamous cell carcinoma of the head and neck, www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst November 24, 2015; DOI: 10.1158/1078-0432.CCR-15-2209 Romick-Rosendale et al. Second, using HPV-immortalized human keratinocytes, we Translational Relevance have previously reported that FANCA or FANCD2 knockdown Head and neck squamous cell carcinoma (HNSCC) is a drive proliferation and HPV E7–dependent hyperplasia in three- devastating cancer type with poor outcomes particularly when dimensional (3D) organotypic epithelial raft but not in two- diagnosed at advanced, invasive stages. Targetable genes and dimensional keratinocyte culture systems (20). Third, we have pathways that stimulate HNSCC progression remain poorly recently reported that defects in the FA pathway stimulate HPV understood. A significant proportion of HNSCCs harbor genome amplification and accumulation of the HPV E7 onco- mutations in FA DNA repair genes. Furthermore, individuals protein with concomitant cellular proliferation (21, 22). Fourth, with germline loss-of-function mutations in FA genes are FA patient–derived HNSCC cell lines were shown to harbor either uniquely predisposed to aggressive HNSCC development. similar or increased stem cell populations when compared with Herein, we show that loss of the FA pathway in HNSCC cells sporadic HNSCC lines, using tumor sphere formation, CD44 stimulate plasma membrane reorganization and tumor cell positivity, or ALDH1 status as experimental end points (23, 24). invasiveness in vitro and in vivo, that is reliant upon NHEJ- To define the functional effects of acquired FA deficiency in associated DNA-dependent protein kinase (DNA-PK) and HNSCC cells, we generated isogenic FA HNSCC models using Rac1 GTPase. These findings implicate this important DNA shRNA-mediated stable knockdown and rescue strategies in HPV- repair pathway in the suppression of advanced tumor pheno- positive and -negative tumor cell lines. While depletion of the key types, and identify new treatment options tailored to FA- FA pathway components FANCA, FANCD2, and FANCJ induced deficient HNSCCs. classical FA phenotypes in these cells when exposed to DNA crosslinkers, minor to no effects on tumor cell growth were observed under standard culture conditions. Surprisingly, how- ever, under these same conditions, FA loss caused cytoskeletal esophageal, and anogenital regions. In fact, FA patients with reorganization and dramatic increases in tumor cell invasiveness HNSCCs are usually diagnosed at a young age with advanced in the absence of proliferative gains in HPV-positive and negative tumor stages that have a poor prognosis (9, 10). FA has been HNSCC cells. Invasive properties were associated, at least in part, associated with recessive mutations in one of 19 FA genes (11), with increased activities of the NHEJ-associated DNA-dependent which play a crucial role in triggering and coordinating funda- protein kinase (DNA-PK) and the Rac1 GTPase, thus linking FA- mental mechanisms of DNA repair for the maintenance of associated DNA damage responses with cytoskeletal machineries. genome instability. When intact, the FA core complex, composed In summary, these data highlight new and unexpected signaling of the protein products of eight FA genes including FANCA, is connections between the FA DNA repair pathway and invasive assembled at the site of DNA damage and triggers monoubiqui- tumor phenotypes in HNSCC. These might be targeted for the tination of the central and evolutionarily conserved pathway development of novel treatment strategies to lower mortality and members FANCD2 and FANCI by the E3 ligase FANCL. The improve the prognosis of patients with advanced HNSCCs. activated FANCD2/FANCI dimer then stabilizes the stalled rep- lication fork at the crosslink and coordinates the activity of nucleases, TLS polymerases, and homologous recombination Materials and Methods factors.
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