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研究生：	趙鈺瑛 Chao, Yu-Ying
論文名稱：	探討初級纖毛在麩醯胺酸缺失適應下誘導胰臟癌轉移中所扮演的角色 Investigate the role of primary cilia in pancreatic cancer metastasis under glutamine-deficient microenvironment
指導教授：	王家義 Wang, Chia-Yih
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2025
畢業學年度：	113
語文別：	英文
論文頁數：	102
中文關鍵詞：	初級纖毛、胰管腺癌、癌轉移、麩醯胺酸
外文關鍵詞：	Primary cilia, Pancreatic ductal adenocarcinoma, metastasis, Glutamine
相關次數：	點閱：19 下載：1
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癌轉移和結締組織過度增生是胰管腺癌的特徵。結締組織增生的腫瘤微環境會造成養分缺失，其中麩醯胺酸是在胰管腺癌中減少最多的氨基酸。然而，麩醯胺酸缺失和癌轉移的相關性目前還有許多未知。為了解決這個問題，我們培育了具有和正常胰管腺癌細胞有相同生長速率且對長時間麩醯胺酸缺失具有適應性的胰管腺癌細胞（-QQ細胞）。我們發現，麩醯胺酸缺失會透過誘導初級纖毛生成以促進上皮細胞在胰管腺癌癌化過程會逐漸消失。我們應用RNA定序法找到了MLPH是誘導初級纖毛重新生成的重要調控者。臨床檢體中，高度表達MLPH的患者會和癌轉移與較差的預後有正相關性。MLPH會位在中心體上並促進初級纖毛重新生長。初級纖毛會上調PLCG1以促進癌轉移的發生。有趣的是，PLCG1會位在初級纖毛上，當剔除PLCG1會降低初級纖毛生成，代表PLCG1會對初級纖毛有正回饋的調控。我們的研究揭露了在麩醯胺酸缺失時MLPH-初級纖毛-PLCG1對於加速胰臟癌轉移的關聯性。這將會提供新的胰管腺癌治療方式。

Metastatic spread and desmoplasia are the features of pancreatic ductal adenocarcinoma (PDAC). The desmoplastic microenvironment causes nutrient-poor environment, and the most deficient amino acids in PDAC tumors is glutamine (Gln). However, the relationship between the Gln-poor microenvironment and cancer metastasis remains unclear. To address this issue, we generated clonal Gln-adapted PDAC (-QQ) cells that adapt to long-term Gln-deficient treatment, and their proliferative capacities were equal to parental cells. Here we demonstrate the Gln-deficient environment promotes PDAC metastasis through epithelial-mesenchymal transition (EMT) process via induction of primary ciliogenesis. Primary cilia are widely observed in almost all human cells to maintain cellular function; however, they are gradually absent under PDAC progression. We applied RNA sequencing and identified melanophilin (MLPH) as the critical mediator of primary cilia regrowth. Clinically, elevated MLPH expression in PDAC correlates with adverse patient outcomes and increased metastatic incidence. Mechanistically, MLPH is recruited to the centrosome where it drives the reassembly of primary cilia under chronic glutamine deprivation. Primary ciliogenesis subsequently induces the transcriptional upregulation and ciliary recruitment of phospholipase C γ1 (PLCG1), activating downstream EMT and invasion programs. Remarkably, inhibition of PLCG1 not only impairs metastatic behaviors but also disrupts ciliogenesis itself, revealing a positive feedback loop that reinforces ciliary assembly. Together, these findings delineate a novel MLPH–primary cilia–PLCG1 signaling axis that enables PDAC cells to adapt to nutrient‐limiting microenvironments and promotes metastatic dissemination; this axis represents a promising target for therapeutic intervention in pancreatic cancer.

博士論文合格證明書	1
中文摘要	2
Abstract	3
Acknowledgments	4
Contents	6
Introduction	9
Pancreatic cancer: Epidemiology, treatments, and challenges	9
Pancreatic cancer metastasis	10
Pancreatic cancer desmoplasia tumor microenvironment	12
The role of glutamine	13
The function of primary cilia	14
The function of melanophilin (MLPH)	15
The function of phospholipase C gamma 1 (PLCG1)	16
Results	18
Generation of –QQ cells adapted to prolonged glutamine deficiency for three months.	18
Glutamine deprivation contributes to PDAC EMT and metastasis.	20
Primary cilia play critical roles in PDAC EMT and metastasis upon Gln deficiency.	22
MLPH induces primary cilia formation under glutamine deficiency.	25
MLPH promotes primary cilia formation for inducing PDAC metastasis under glutamine deprivation	28
Primary cilia upregulate phospholipase C gamma 1 (PLCG1) to facilitate PDAC metastasis.	31
Discussion	34
Materials and Methods	37
Figures	48
Figure 1. PDAC cells regain the ability to proliferate under long-term Gln deficiency.	48
Figure 2. Glutamine deprivation for three months does not induce senescence.	49
Figure 3. Distinct signaling pathways are activated in -QQ PANC-1 cells.	50
Figure 4. Glutamine deprivation promotes cell migration and invasion in PANC-1 PDAC cells.	51
Figure 5. Matrix metalloproteinases (MMPs) activities were enhanced in -QQ cells.	52
Figure 6. Glutamine deficiency induces the EMT process.	54
Figure 7. Glutamine deprivation actuates PDAC spheroids invasion.	55
Figure 8. Glutamine deprivation induces primary ciliogenesis.	56
Figure 9. Disruption of primary cilia blocks EMT, migration, and invasion in -QQ cells.	59
Figure 10. Disruption of primary cilia retards PDAC spheroid invasion ability.	61
Figure 11. MLPH was upregulated in –QQ cells.	62
Figure 12. MLPH levels were positively correlated with PDAC tumorigenesis.	63
Figure 13. MLPH upregulation was highly correlated with poor prognosis in PDAC patients.	65
Figure 14. MLPH upregulation was highly correlated with PDAC metastasis and poorer prognosis in PDAC patients.	66
Figure 15. MLPH promotes primary cilia formation under glutamine deprivation	67
Figure 16. MLPH is recruited to centrosome to induce primary cilia formation under glutamine deprivation.	69
Figure 17. MLPH is recruited to centrosome to induce primary cilia formation during G0/G1 phase in cell cycle.	70
Figure 18. The recruitment of MLPH is independent of microtubule assembly.	71
Figure 19. MLPH is targeted to the centrosome independent of MyoVa and Rab27a.	72
Figure 20. MLPH acts as critical mediator in PDAC EMT, cell migration, and cell invasion.	73
Figure 21. Hypoxia-induced cell invasion was not mediated by MLPH upregulation.	74
Figure 22. MLPH upregulation promotes PDAC invasion in the 3D tumor organoids.	75
Figure 23. Gln deprivation promotes EMT, migration, and invasion in luciferase-expressing PANC-1 cells.	76
Figure 24. MLPH did not affect tumor sizes in the orthotopic mouse model.	77
Figure 25. MLPH upregulation promotes PDAC metastasis under Gln deficiency in the orthotopic mouse model.	78
Figure 26. The colonies in the mesentery, spleen, and liver were increased in the -QQ-shScr group but were reduced dramatically in the -QQ-shMLPH group.	80
Figure 27. MLPH promoted pancreatic local invasion.	81
Figure 28. Gln deprivation promotes EMT, migration, and invasion in murine KPC cells.	82
Figure 29. MLPH did not affect tumor sizes in the KPC orthotopic mouse model.	83
Figure 30. The colonies in the mesentery, spleen, and liver were increased in the -QQ-shScr group but were reduced dramatically in the -QQ-shMLPH group.	84
Figure 31. MLPH promoted pancreatic local invasion in KPC orthotopic mouse model.	86
Figure 32. Glutamine deprivation upregulated phospholipase C gamma 1 (PLCG1).	87
Figure 33. Upregulation of phospholipase C gamma 1 (PLCG1) is correlated to PDAC tumorigenesis.	88
Figure 34. Phospholipase C gamma 1 (PLCG1) upregulation promote PDAC EMT, migration, and invasion.	89
Figure 35. Primary cilia upregulate phospholipase C gamma 1 (PLCG1) to facilitate PDAC metastasis.	91
Figure 36. Primary cilia-mediated PLCG1 activation contributed to maintaining primary cilia formation in the feedback loop.	92
Figure 37. Graphic abstract	94
References	95
                                    

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