Abstract 4743: Wnt/beta-catenin mediated epigenetic modifications drive age-dependent oral squamous cell carcinoma evolution

Abstract

Oral Squamous Cell Carcinoma (OSCC) is a devastating disease associated with high morbidity, poor survival, and few therapeutic options. This malignancy is driven, in part, by epigenetic reprogramming of the chromatin landscape directed by β-catenin in complex with CREB-binding protein (CBP) and mixed lineage leukemia methyltransferase 1 (MLL1). The β-catenin/CBP/MLL1 complex promotes an open chromatin structure by enabling transcription of genes associated with cell plasticity, including cancer stem cells and cells with partial EMT (p-EMT) phenotypes. Growing evidence indicates that cell plasticity and cellular senescence are integral processes shared by cancer and aging. Given that the median age of OSCC diagnosis is 66 years, it is likely that aging promotes OSCC evolution to advanced disease. To examine the effects of aging on OSCC evolution, we adapted a syngeneic mouse model of tobacco-associated oral carcinogenesis. This model utilizes a mouse cell line, 4MOSC1, derived from 4-nitroquinoline-1 oxide- (4NQO)-induced tongue tumor which, when implanted into mouse tongues, generates tumors that recapitulate human OSCC mutanome. The growth of 4MOSC1 derived orthotopic tumors was studied in 6- and 80-week-old mice. Tumors were allowed to develop for 18 days, after which they were harvested and processed for single cell RNA sequencing, histopathology and immunofluorescence (IF) analyses. Results showed that tumors grew at a faster rate and to a greater overall size in old mice compared to their young cohorts. OSCC harvested from the old mice displayed statistically significant reduction in membranous E-cadherin concomitant with increased Cbp and H3K4me3 abundance, suggesting an age-associated upregulation of β-catenin/Cbp/Mll1 epigenetic activity. Increased expression of Bmi1, keratin 14, and podoplanin supported increased cell plasticity in OSCC from aged mice. Further, these tumors exhibited augmented cellular senescence, as judged by the disruption of lamin B1-associated nuclear membrane integrity, and by an increased cell population with markers of senescence from single cell sequencing analyses. These data suggest that aging is associated with increased β-catenin/Cbp/Mll1 epigenetic signaling, cell plasticity and cellular senescence, which collectively contribute to the evolution of OSCC. Citation Format: Emily R. Fisher, Anthony Spinella, Nina C. Hardy, Xaralabos Varelas, Manish Bais, Maria A. Kukuruzinska. Wnt/beta-catenin mediated epigenetic modifications drive age-dependent oral squamous cell carcinoma evolution. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4743.