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.
Purpose Cancer is one of the leading causes of death worldwide. Patient-derived tumor cells can serve as a powerful resource for studying pathophysiologic mechanisms and developing robust strategies for precision medicine. To address this problem, we launched the patient-derived organoids (PDOs) Hub to establish a comprehensive model of various tumor organoids from pancreatic, biliary tract, liver, colorectal, breast, gastric, ovarian, and oral cancers, with matching clinical data and molecular characteristics. Methods All specimens were collected from histologically confirmed cancer patients at the National Cancer Center. Samples obtained from surgery, biopsy, or body fluid (malignant ascites or pleural effusion) were collected for ex vivo culture of tumor cells. PDOs were managed according to our standard operating procedure (SOP), which included specimen delivery process, separation of cells from tissues, criteria for subculture, quality control (QC), production of genomic and histologic data, and the 384-well-based drug response evaluation system. Organoids were considered to be successfully cultured when they were maintained for five or more passages. Results A total of 263 PDOs were established from various cancer types, including oral cancer (N = 89), pancreatic cancer (N = 48), ovarian cancer (N = 32), breast cancer (N = 30), biliary tract cancer (N = 29), hepatocellular carcinoma (N = 17), gallbladder cancer (N = 8), gastric cancer (N = 7) and colorectal cancer (N = 3). PDOs broadly recapitulated the histologic and genetic characteristics of the patient’s tumor. These organoids available for long-term culture were cryopreserved, and a total of 2986 stocks have been accumulated. Drug screening tests were performed with 60 PDOs (pancreatic cancer, N = 36; breast cancer, N = 15; ovarian cancer, N = 6; gastric cancer, N = 3) using selected agents among the 47 drugs for each type of cancer. Profiles of cytotoxic agents were well correlated with the patient’s clinical responses to the matched drugs and tested investigational agents also showed promising antitumor activity. Conclusions We have established a model of several human cancer organoids. This will serve as the platform that can recapitulate the physiology and drug response profiles of human cancer and pave the way for screening innovative drugs, identifying novel targets, and stratifying patients for pertinent therapeutic options. (This work was supported by National Research Foundation of Korea grant, funded by the Korean government (MSIT) (No. 2020M3A9A5036362)) Citation Format: Yebeen Yu, Mi Rim Lee, Wonyoung Choi, Sumin Kang, Jeong Eun Gong, Soobeen Heo, Hye Ju Park, Sang Myung Woo, So-Youn Jung, Sung Weon Choi, Jong-Ho Lee, Myong Cheol Lim, Ji Yeon Baek, Bo Hyun Kim, Ji Hoon Kim, Yuri Cho, Sang-Jae Park, Yun-Hee Kim, Sun-Young Kong. Patient-derived organoids (PDOs) hub of National Cancer Center, Korea: pre-clinical model for drug screening [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 161.
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive disease with a poor prognosis and a limited response to most of the treatments. Despite a platinum-based drug such as oxaliplatin or cisplatin is one of the most effective chemotherapy drugs for PDAC, resistance to it is a major limiting factor in PDAC treatment, indicating an urgent need for new approaches. Recently, targeting major DNA damage response (DDR) regulators such as ATM (Ataxia-telangiectasia mutated) or ATR (Ataxia telangiectasia mutated and Rad3-related) kinase has shown therapeutic potential in cancer treatment. This shows that it may be possible to enhance the responsiveness of platinum medicines via a DDR inhibition strategy. The most recently developed ATR inhibitor with the greatest potency, BAY 1895344, showed an anti-proliferative effect in clinical trials. Here, we aimed to evaluate the effect of ATR inhibition using BAY 1895344 on responsiveness to oxaliplatin in pancreatic cancer, for the first time. CFPAC-1 and Capan-2 are selected among six kinds of pancreatic cancer cell lines as oxaliplatin-sensitive and -resistant cells, respectively. According to BRAID analysis, combining the BAY 1895344 and oxaliplatin resulted in strong synergistic effects in both cell lines, particularly in Capan-2. The synergism is also confirmed in all four organoids derived from PDAC patients. We found that p-Chk1, coordinating DDR and cell cycle checkpoint, was considerably suppressed by the combined treatments, which was associated with elevated γ-H2AX intensity, cell cycle arrest and apoptosis. Moreover, we investigated the in vivo synergistic anti-tumor efficacy of combination therapy using a tumor-bearing nude mice model with CFPAC-1 and Capan-2 cells, demonstrating a substantial reduction of tumor growth in combination therapy when compared to single treatment. In conclusion, ATR inhibition enhanced the anticancer effect of oxaliplatin, and this combined therapeutic strategy may be effective in overcoming chemo-resistance in PDAC. (This study is supported by National Cancer Center, Republic of Korea (No. 2212470, 2010330)) Citation Format: Hye Won Shon, Jung Won Chun, Jeong Eun Gong, Mi Rim Lee, Yu-Sun Lee, Sumin Kang, Sunshin Kim, Sang Myung Woo, In Rae Cho, Woo Hyun Paik, Woo Jin Lee, Ji Kon Ryu, Yong-Tae Kim, Sang Hyub Lee, Yun-Hee Kim. Inhibiting ataxia-telangiectasia mutated and RAD3-related (ATR) by BAY 1895344 overcomes chemoresistance to oxaliplatin and promotes synergistic anti-tumor effect in pancreatic cancer [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 6217.
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