title: Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis.
abstract: Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60-80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis.
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Coppock
authors.affiliation: Department of Biology, University of South Dakota, Vermillion, South Dakota, USA.|Department of Computer Science, University of South Dakota, Vermillion, South Dakota, USA.
authors.forename: Erliang
authors.initials: E
authors.lastname: Zeng
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lee
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.|Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, South Dakota, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Spanos
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Onken
authors.affiliation: Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Uppaluri
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.|Department of Otolaryngology/Head and Neck Surgery, Sanford Health, Sioux Falls, South Dakota, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Cancer Biology Research Center, Sanford Research, Sioux Falls, South Dakota, USA.
authors.forename: Paola D
authors.initials: PD
authors.lastname: Vermeer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor
keywords: head and neck oral cancer; human papillomavirus; metastasis; recurrence