Abstract 1846: HPV oncoproteins cause specific types of chromosomal instability in head and neck cancer

Abstract

Abstract Aneuploidy, a karyotype that differs from a multiple of the haploid, is a hallmark of cancer. Aneuploidy can be caused by an ongoing rate of chromosome missegregation during mitosis, known as whole chromosomal instability (CIN). Work from our lab and others has shown that while low rates of CIN can promote tumorigenesis, high levels of CIN are tumor suppressive. Combining two insults that each cause low CIN results in high CIN, cell death, and tumor suppression. We recently showed that the chemotherapy drug paclitaxel causes CIN due to multipolar divisions in breast cancer. Preliminary evidence suggests that tumors which exhibit CIN prior to therapy are sensitized to paclitaxel because it increases their level of CIN over a maximally tolerated threshold. Radiation also induces CIN, and rectal adenocarcinomas which exhibit CIN prior to treatment are sensitized to chemoradiation therapy. Human papillomavirus (HPV), specifically HPV subtype 16, is a growing cause of head and neck cancer worldwide. In cervical cancer, HPV is associated with CIN, which has been attributed largely to the expression of its E6 and E7 oncoproteins. HPV+ head and neck cancer patients show improved responses to radiation therapy than HPV- head and neck patients, potentially due to an increased basal rate of CIN. Here, we tested the ability of HPV E6, E7, or E6+E7 expression to induce CIN in normal oral keratinocytes (NOKs). Expression of E6 alone robustly induced misaligned chromosomes and multipolar spindles with supernumerary centrosomes, while E7 expression alone produced more moderate effects. Combined expression of E6 and E7 exacerbated the phenotypes observed in NOKs expressing E6 alone. Expression of E6, either alone or in combination with E7 caused reduced protein levels of the mitotic kinesin CENP-E, which is sufficient to induce misaligned chromosomes. Interestingly, HPV+ patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma showed less evidence of mitotic defects than NOKs expressing E6 alone. A subset of HPV+ PDX tumors showed an increase in misaligned chromosomes when compared to HPV- tumors, but no increase in lagging chromosomes or multipolar spindles was observed. Together, these data suggest HPV infection causes an incompletely penetrant increase in specific types of CIN in head and neck cancer and that a basal rate of CIN may be predictive of treatment response independent of HPV status. Citation Format: Laura C. Funk, Denis L. Lee, Randall J. Kimple, Paul F. Lambert, Beth A. Weaver. HPV oncoproteins cause specific types of chromosomal instability in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1846.