實驗室研究方向-- CTP合成酶線狀結構如何影響癌症的形成和影響果蠅的發育-白麗美老師
我的研究聚焦於探討CTP合成酶線狀結構（Cytidine Triphosphate Synthase Filament，簡稱CTPS filament）如何影響癌症形成及果蠅（Drosophila melanogaster）發育。我們整合遺傳學、蛋白質體學、代謝體學與基因體學等多重實驗方法，深入分析癌細胞在營養壓力下的逆境生存機制，並揭示細胞內生化反應區域化（compartmentalization）對果蠅發育的關鍵作用。
CTP合成酶（CTPS）是細胞存活與生長不可或缺的酵素，負責催化CTP合成，後者在DNA、RNA、脂質合成及醣化反應中均扮演重要角色。我們首次在果蠅生殖細胞（卵室）中觀察到CTPS形成線狀結構。此前研究已證實，CTPS的聚集能調控其酶活性，以滿足卵室濾泡細胞（follicle cells）中DNA快速複製的需求，顯示生化反應區域化對細胞生理的深遠影響。
Masaru Goto et.al.,Structure,2004
CTPS線狀結構普遍存在於細菌、酵母菌、線蟲、果蠅及人類細胞中，表明生化反應的區域化調控是一種演化上高度保守的機制，具有重要生理意義。此外，多種癌症患者中常見CTPS過度表達，提示其可能在腫瘤形成中發揮作用。
腫瘤形成通常源於癌細胞異常增生，伴隨細胞生長相關基因（如致癌基因，oncogene）變異。同時，癌細胞會重塑代謝途徑，高度依賴葡萄糖、麩醯胺酸及特定胺基酸作為營養來源，以支持快速增殖。然而，腫瘤內部常因資源耗竭而面臨麩醯胺酸缺乏的壓力。在此營養逆境下，癌細胞透過形成CTPS線狀結構調整代謝反應，實現生存適應。
目前，對於此類癌細胞的生理特性了解有限，但我們的研究顯示，CTPS線狀結構的形成促進了腫瘤生長。我們進一步發現，蛋白質轉譯後修飾（如泛素化與甲基化）可調節CTPS聚集，影響生化反應的區域化。此外，胺基酸（如組胺酸與天門冬胺酸）的供應亦能動態調控CTPS線狀結構的形成。
透過基因體、代謝體與蛋白質體分析，我們逐步揭示癌細胞在營養壓力下的應對機制，並探索其如何調控CTPS線狀結構的動態平衡。我們希望進一步研究此逆境生存策略是否可作為標靶藥物的新靶點，為癌症治療開闢新方向。
研究重點
1. 探討果蠅生殖細胞（卵室與精子）中CTPS線狀結構的形成機制及其與細胞週期和細胞分化的關聯。
2. 解析癌細胞在麩醯胺酸缺乏的營養逆境中調控CTPS線狀結構的機制。
3. 研究CTPS線狀結構形成的分子機制是否可作為標靶藥物的潛在靶點。
通過這些研究，我們旨在闡明CTPS線狀結構在細胞生理與腫瘤形成中的作用機制，為開發新型抗癌療法提供理論基礎。
The Research Direction – How the Linear Structure of CTP Synthase Affects Cancer Formation and Influences the Development of Drosophila,
Li-Mei Pai PhD.
My research focuses on investigating how the cytidine triphosphate synthase filament (CTPS filament) influences cancer development and the development of Drosophila melanogaster (fruit fly). By integrating genetics, proteomics, metabolomics, and genomics, we explore the survival mechanisms of cancer cells under nutritional stress and elucidate the critical role of biochemical reaction compartmentalization in fruit fly development.
CTP synthase (CTPS) is an essential enzyme for cell survival and growth, catalyzing the synthesis of CTP, a molecule vital for DNA, RNA, lipid synthesis, and glycosylation reactions. We first observed the formation of CtpSyn filaments in the germline cells (ovarian chambers) of fruit flies. Previous studies have demonstrated that CTPS aggregation regulates its enzymatic activity to meet the demands of rapid DNA replication in follicle cells of the ovarian chamber, highlighting the profound impact of biochemical reaction compartmentalization on cellular physiology.
Masaru Goto et.al.,Structure,2004
CTPS filaments have been observed across various organisms, including bacteria, yeast, nematodes, fruit flies, and human cells, suggesting that the compartmentalized regulation of biochemical reactions is an evolutionarily conserved mechanism with significant physiological implications. Moreover, CTPS is frequently overexpressed in multiple cancer types, indicating its potential role in tumorigenesis.
Tumorigenesis typically arises from the abnormal proliferation of cancer cells, often driven by mutations in genes associated with cell growth (e.g., oncogenes). Concurrently, cancer cells rewire their metabolic pathways, heavily relying on glucose, glutamine, and specific amino acids as nutrient sources to sustain rapid proliferation. However, cells within tumors often face glutamine depletion due to resource exhaustion. Under such nutritional stress, cancer cells adapt by forming CTPS filaments to modulate metabolic reactions, enabling survival in adverse conditions.
While the physiological characteristics of these cancer cells remain poorly understood, our research demonstrates that CTPS filament formation promotes tumor growth. We further found that post-translational modifications of proteins, such as ubiquitination and methylation, regulate CTPS aggregation, thereby influencing biochemical reaction compartmentalization. Additionally, the availability of amino acids (e.g., histidine and asparagine) dynamically modulates CTPS filament formation.
Through genomic, metabolomic, and proteomic analyses, we are progressively uncovering the mechanisms by which cancer cells cope with nutritional stress and regulate the dynamic balance of CTPS filaments. We aim to further investigate whether this adaptive survival strategy could serve as a potential target for precision therapeutics, offering new avenues for cancer treatment.
Research objectives
(a) Investigating the formation mechanisms of CTPS filaments in fruit fly germline cells (ovarian chambers and sperm) and their connections to the cell cycle and cellular differentiation.
(b) Dissecting how cancer cells regulate CTPS filament formation under glutamine-deficient nutritional stress.
(c) Exploring whether the molecular mechanisms underlying CTPS filament formation could serve as potential targets for therapeutic intervention.
Through these studies, we seek to elucidate the role of CTPS filaments in cellular physiology and tumorigenesis, providing a theoretical foundation for the development of novel anticancer therapies.