Abstract 1327: Mechanism of tumor microenvironment remodeling and progression based on FAM20C-mediated extracellular kinome network in oral squamous cell carcinoma

Abstract

Abstract Tumorigenesis and tumor growth are accomplished through the crosstalk between intra- and extracellular molecules, which is often mediated by phosphorylation, and research on intracellular signal transduction has made great progress. Despite the significance of the tumor microenvironment (TME) for tumor progression, relatively few kinome studies have been conducted on phosphorylation cascade in the TME of oral squamous cell carcinoma (OSCC). OSCC is an aggressive cancer with a high recurrence rate of 40-60%, but there are uncertain molecular classification and no identifiable driver mutation genes to be a druggable target. As the presence of extranodal extension (ENE) is currently the most significant risk factor for locoregional recurrence or distant metastasis, differences in molecular profiles between patients with and without ENE may provide insight into regulatory mechanisms that are critical for the recurrence and progression of OSCC. Using LC-MS-based secretome analysis, we examined total and phosphoproteins from ten patients' plasma with or without ENE. Global proteome analysis revealed that the ENE group had higher levels of protein phosphorylation, the ERK 1/2 cascade, signal transduction, phagocytosis, and the integrin-mediated signaling pathway than the without ENE group. Furthermore, 319 phosphosites originating from 165 proteins were discovered, with the majority of phosphorylated proteins having lipid binding, complement system, extracellular matrix, and calcium binding. Interestingly, we discovered 82 proteins with Ser-x-Glu/pSer sites among the phosphorylated proteins, indicating that they could be substrates of the unique extracellular secreted serine kinase, family with sequence similarity 20C (FAM20C). Proteins associated to tumor metastasis, such as insulin-like growth factor-binding proteins (IGFBPs), osteopontin (OPN), and serine protease inhibitors (Serpins), are known as substrates for the FAM20C. In accordance with the proteome results in plasma, gene ontology (GO) term analysis using the NanoString oncology panel revealed that extracellular structure organization-related genes were up-regulated and enzyme inhibitor, kinase regulator, and protein tyrosine kinase activity-related genes were down-regulated in human OSCC cell line, Cal-27, with knockout of FAM20C. Furthermore, we functionally demonstrated that FAM20C depletion inhibited invasion by lowering protein production of Vimentin, TGF-β, and ERK phosphorylation. Collectively, we discovered that the secreted kinase FAM20C controls metastasis by cross-talking with proteins in the TME and propose that this may be the evidence for OSCC prognosis. (This research was supported by National Cancer Center, Korea (No. 2210980) and National Research Foundation of Korea grant funded by the Korea government (No. 2020M3A9A5036362)). Citation Format: Mi Rim Lee, Yu-Sun Lee, Sumin Kang, Hye Won Shon, Jeong Eun Gong, Hye Joo Park, Jung-Ah Hwang, Kyung-Hee Kim, Sung Weon Choi, Yun-Hee Kim. Mechanism of tumor microenvironment remodeling and progression based on FAM20C-mediated extracellular kinome network in oral squamous cell carcinoma [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 1327.