Abstract 3911: A FGFR-p53 developmental signaling axis drives progression of salivary cancer
Authors: Billington Julia M. , Musicant Adele M. , Cote Jessica L. , Modliszewski Jennifer , Tsai Yi-Hsuan , Landuau Luane J. , Powers John , Betancourt Renee , Sekhri Radhika , Padilla Ricardo J. , Hernandez-Prera Juan C. , Hayes David N. , Hackman Trevor G. , Gokcumen Omer , Knox Sarah M. , Guidice Jimena , Amelio Antonio L. 
Published: March 2024

Abstract
Mucoepidermoid carcinoma (MEC) is the most frequently occurring salivary gland (SG) malignancy. Treatments for high grade (HG) MEC are lacking due to a limited understanding of its diverse histological and clinical features. Consequently, patients with non-resectable HG MEC are often treated with adjuvant radiotherapy and suffer from increased rates of recurrence and metastasis with poor 5-year survival rates (30-50%) as compared to low grade (LG) MEC (76-95%). We previously demonstrated a role for IGF-1 signaling, an important mediator for SG development and branching morphogenesis, in MEC pathogenesis (Musicant et al, 2021). Here, we analyzed transcriptome profiles shared between fetal and adult normal parotid (PAR) tissues with MEC tumors to investigate programs involved in MEC progression. Using this information, we developed the first genetically engineered mouse model (GEMM) of advanced HG MEC via targeted oncogene expression in SG ductal cells. MEC samples from 21 PAR tumors (8 LG/13 HG), 8 age-matched normal, and 3 fetal PAR glands aged between 22-24 weeks of gestation (Saitou et al, 2020) were retrospectively collected from UCSF or UNC Surgical Pathology. RNAseq was performed on FFPE samples using Illumina HiSeq. Differential gene expression, gene set enrichment analyses (GSEA), and alternative splicing analyses were compared between fetal/normal/MEC according to tumor grade and CRTC1 (CREB-regulated transcription coactivator 1)/MAML2 (Mastermind-like 2) (C1/M2) status. Based on these analyses, we developed a GEMM combining C1/M2 expression with TP53 loss. GEMM tumors were subjected to RNAseq and reviewed by two independent pathologists for diagnostic confirmation of HG MEC.GSEA revealed significant overlap between MEC tumors and fetal SG for genes governing proliferation and developmental pathways associated with branching morphogenesis. Interestingly, upregulation of the negatively regulated p53 target FOXM1 along with a mutant-p53 gene signature (Troester et al, 2006) revealed that p53 dysregulation in HG tumors phenocopies that seen in fetal SG. Cre-inducible expression of C1/M2 alone was insufficient to induce MEC-like lesions when targeted to distinct salivary cell types (ductal Krt14-CreER, acinar Mist1-CreER, serous demilune Dcpp1-CreER). However, p53 alteration (Tp53KO) with ductal C1/M2 expression drove MEC formation with histological and molecular features of human HG-MEC. Notably, transcriptome profiles implicate an FGFR-p53 developmental signaling axis in MEC progression. Our autochthonous GEMM recapitulates advanced HG-MEC in vivo providing the field with a powerful platform for identifying pathways for developing targeted therapies. Taken together, the integrated bioinformatics and mouse modeling of this study provide a critical step toward elucidating salivary MEC progression and suggest a role for FGFR targeted therapies in the treatment of non-resectable HG MEC.
Citation Format: Julia M. Billington, Adele M. Musicant, Jessica L. Cote, Jennifer Modliszewski, Yi-Hsuan Tsai, Luane J. Landuau, John Powers, Renee Betancourt, Radhika Sekhri, Ricardo J. Padilla, Juan C. Hernandez-Prera, David N. Hayes, Trevor G. Hackman, Omer Gokcumen, Sarah M. Knox, Jimena Guidice, Antonio L. Amelio. A FGFR-p53 developmental signaling axis drives progression of salivary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3911.