活體腫瘤研究模型之建立暨探討ADCK4基因於肺癌腦轉移中扮演的角色

Abstract

肺癌至今仍為全球癌症相關死亡之首要原因，對公共衛生造成重大負擔。根據 2026 年《Global Cancer Statistics》報告，美國預估新增 229,410 例肺癌病例，並造成 124,990 例相關死亡。在臺灣，2023 年肺癌之發生率與死亡率分別為每十萬人口 49.00 例與 21.27 例，且男性之發生率與死亡率均顯著高於女性。儘管近年來手術技術與放射治療已有長足進展，使早期及局限型腫瘤之治療成效明顯提升，轉移性肺癌仍具有高度惡性與不可預測性，且與不良臨床預後密切相關。此外，臨床觀察與基礎研究之間的橫溝，限制了對腫瘤轉移及治療抗性相關分子機制之深入理解。 本研究透過將肺癌細胞注射至小鼠內頸動脈建立體內轉移模型，進行功能喪失 shRNA 篩選，並結合體外及體內功能性實驗及肺癌病患之臨床資料分析，以驗證候選基因之生物學功能與臨床相關性。研究結果顯示，粒線體相關基因 AarF domain-containing kinase 4（ADCK4）為調控腫瘤生成能力與癌症幹性之重要負向調節因子。ADCK4 低表現與較高之腫瘤生成能力、增強之幹細胞特性，以及較差之整體存活率顯著相關。機制上，ADCK4 缺失之癌細胞會發生葡萄糖代謝路徑變化，使葡萄糖代謝由粒線體氧化磷酸化與三羧酸循環（tricarboxylic acid cycle, TCA cycle）轉向醣解作用，此現象符合高度惡性腫瘤常見之 Warburg effect。綜合而言，本研究結果顯示 ADCK4 所介導之代謝調控機制可能作為抑制腫瘤進展、藥物抗性、復發及轉移之潛在治療標的。

Lung cancer remains the leading cause of cancer-related mortality worldwide. According to Global Cancer Statistics 2026, an estimated 229,410 new lung cancer cases and 124,990 lung cancer-related deaths occurred in the United States. In Taiwan, the incidence and mortality rates of lung cancer in 2023 were 49.00 and 21.27 cases per 100,000 population, respectively, with higher rates observed in men than in women Despite remarkable advances in surgical techniques and radiotherapy, which have substantially improved the management of early-stage and localized tumors, metastatic disease remains highly unpredictable and is associated with poor clinical outcomes. Furthermore, the limited integration of clinical observations with experimental investigations has hindered a comprehensive understanding of the molecular mechanisms underlying metastasis and therapeutic resistance. In this study, we performed an in vivo loss-of-function shRNA screen by injecting lung cancer cells into the intracarotid artery of mice, followed by validation of candidate genes through both in vitro and in vivo functional assays and clinical correlation analyses in lung cancer patients. Our results identified the mitochondrial gene AarF domain-containing kinase 4 (ADCK4) as a negative regulator of tumorigenicity and cancer stemness. Reduced ADCK4 expression was associated with enhanced tumorigenic potential, increased stem-like properties, and poorer overall survival in lung cancer patients. Mechanistically, ADCK4-deficient cancer cells exhibited metabolic reprogramming characterized by a shift in glucose utilization from mitochondrial oxidative phosphorylation and the tricarboxylic acid (TCA) cycle toward glycolysis, consistent with the Warburg effect commonly observed in highly aggressive malignancies. Collectively, these findings suggest that ADCK4-mediated metabolic regulation may represent a potential therapeutic target for overcoming tumor progression, drug resistance, recurrence, and metastasis.