含EBV病毒產物之外泌小體經由活化纖維母細胞重塑腫瘤微環境

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李柏儒(Po-Ju Lee) 查詢紙本館藏

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系統生物與生物資訊研究所

論文名稱

含EBV病毒產物之外泌小體經由活化纖維母細胞重塑腫瘤微環境
(EBV Products-containing Exosomes Remodel the Tumor Microenvironment by Activating Stromal Fibroblasts)

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摘要(中)

第三型鼻咽癌與EBV感染有密切關聯且此類型腫瘤組織常有大量免疫細胞浸潤。許多文獻已證實浸潤於鼻咽癌的免疫細胞與癌細胞的交互作用會影響病人預後。另一方面，腫瘤中的纖維化組織與較差的病人預後相關。然而，癌細胞與周邊纖維母細胞之間的相互作用機轉仍待深入探討。在本研究中，我們發現EBV+-鼻咽癌細胞所釋出的外泌小體含EBV潛伏膜蛋白-1(LMP1)及纖維化標誌分子FAP。此外泌小體可被周圍基質環境中的纖維母細胞吞噬，刺激纖維母細胞產生形態上的變化與收縮力的增強，並且活化纖維母細胞進而重塑微環境。轉錄體分析及經QPCR與ELISA驗證結果顯示鼻咽癌的外泌小體明顯影響與組織纖維化功能相關的基因群表現及促發炎細胞激素(IL-6, IL-8, MCP-1)的釋放。此外，細胞實驗結果顯示外泌小體的刺激使纖維母細胞的標誌FAP與活化型YAP1蛋白及其調控的下游分子(CYR61, CTGF, IGFBP3)表現量上升。小鼠腫瘤異體移植實驗結果發現被外泌小體刺激的纖維母細胞會促進腫瘤生長與微環境纖維化。同時，在小鼠腫瘤組織切片染色結果顯示外泌小體刺激使活化型YAP1在間質纖維母細胞中表現量上升，且與FAP表現有正相關性r=0.7671, p=0.0001, Spearman correlation test)。於鼻咽癌病人切片染色結果亦顯示活化型YAP1與FAP的正相關性(r=0.3749, p=0.0157, Spearman correlation test)。這意味著YAP1對調控外泌小體所引發的纖維母細胞活化扮演著重要的角色。使用YAP1的抑制劑Saracatinib 和Verteporfin於纖維母細胞可以有效降低因外泌小體的刺激而誘發的功能性變化，且可抑制纖維母細胞對癌細胞的促生長效應。
綜合以上結果，本研究闡明腫瘤細胞藉由分泌外泌小體與纖維母細胞進行交互作用而導致腫瘤組織趨向一個有利於癌症進展的微環境，提供以YAP1抑制劑瓦解鼻咽腫瘤微環境而達到抑制癌細胞生長的理論基礎。

摘要(英)

Type Ш nasopharyngeal carcinoma is closely associated with EBV-infection and characterized by heavy lymphocyte infiltration. It is recognized that interactions between cancer cells and immune cells have profound effects on patients’ outcomes. Further, fibrotic response in the tumor tissue is correlated with poorer prognosis in NPC patients. Nevertheless, the intercommunications between stromal fibroblasts and NPC cells remain relatively unexplored. In the present study, we found that exosomes derived from EBV+NPC cells contained EBV-encoded latent membrane protein 1 (LMP1) and FAPprotein. Treating fibroblasts derived from NPC biopsies with these exosomes induced morphological changes and an enhanced contraction ability. Results of transcriptomic analyses revealed that exosome stimulation in fibroblasts predominantly affected expression of genes involved in function of fibrotic response. Fibrosis-associated genes such as IL-6, IL-8, and MCP-1 were validated by QPCR and ELISA assays. Exosome stimulation induced fibroblast activation as evidenced by increased expressions of FAP active YAP1, and YAP1 downstream molecules (CYR61, CTGF, IGFBP3). Results of mouse xenografted model demonstrated that exosome-stimulated fibroblasts promoted tumor growth. Immunohistochemical data showed a positive correlation between expressions of FAP and active YAP1 (r=0.7671 and p=0.0001, Spearman correlation test). An enhanced fibrotic response was noticed within exosome-treated tumors. The association among active YAP1, FAP, and fibrotic response were also found in human NPC biopsies (r=0.3749 and p=0.0157, Spearman correlation test). Targeting YAP1 by utilizing Saracatinib and Verteporfin markedly blunted EBV exosomes-mediated fibroblast activation and functional effects.
Collectively, our data provide evidence to better understand the interactions among EBV,
NPC cells, and stromal fibroblasts via exosomal transmission, which facilitates the establishment of a pro-tumor microenvironment. Furthermore, our data suggest that the use of YAP1 inhibitors might be a potentially effective strategy in treating NPC with desmoplastic response within tumors.

關鍵字(中)

★ EBV病毒
★ 外泌小體
★ 纖維母細胞
★ 腫瘤微環境

關鍵字(英)

★ EBV
★ exosomes
★ fibroblast
★ tumor microenvironment

論文目次

中文摘要 ................................................................................................................................ i
英文摘要 ................................................................................................................................ ii
誌謝 ................................................................................................................................ iii
目錄 ................................................................................................................................ iv
圖目錄 ................................................................................................................................ viii
表目錄 ................................................................................................................................ ix
符號說明 ................................................................................................................................ x
Chapter 1 Introduction............................................................................................................. 1
1-1 Epstein-Barr Virus (EBV) ..................................................................................... 1
1-1-1 EBV-positive Nasopharyngeal Carcinoma (NPC)................................................. 1
1-2 Exosome................................................................................................................. 2
1-2-1 EBV-related Exosome............................................................................................ 4
1-3 Tumor Microenvironment....................................................................................... 4
1-3-1 Cancer-associated Fibroblasts (CAFs).................................................................... 5
1-3-2 CAFs in the NPC TME........................................................................................... 6
1-4 Fibroblast Activation Protein (FAP)....................................................................... 7
1-5 Yes-associated Protein 1 (YAP1) .......................................................................... 8
1-5-1 Role of YAP1 in fibroblasts................................................................................... 9
Chapter 2 Materials and Methods............................................................................................ 10
2-1 Cell culture.............................................................................................................. 10
2-2 Exosome isolation................................................................................................... 10
2-3 Electron Microscopy (EM) analysis....................................................................... 10
2-4 Exosome labelling................................................................................................... 11
2-5 Live cell imaging.................................................................................................... 11
2-6 Immunocytochemistry (ICC).................................................................................. 12
2-7 Western blotting...................................................................................................... 12
2-8 Collagen contraction assay..................................................................................... 13
2-9 Drug toxicity assay................................................................................................. 13
2-10 Immunohistochemistry (IHC)................................................................................. 14
2-11 Transcriptomic analysis.......................................................................................... 15
2-12 Quantitative polymerase reaction (QPCR) ............................................................ 15
2-13 Enzyme-Linked Immunosorbent Assay (ELISA) .................................................. 16
2-14 Animal studies........................................................................................................ 16
2-15 Statistics.................................................................................................................. 17
Chapter 3 Results…………………......................................................................................... 18
3-1 Fibroblasts identified in NPC tissue sections......................................................... 18
3-2 Uptake of EBV products-containing exosomes in primary fibroblasts.................. 18
3-3 EBV product-containing exosomes alter morphology in fibroblasts...................... 19
3-3-1 EBV product-containing exosomes enhance cell contraction ability in fibroblasts 19
3-4 Exosomes modulate fibrotic-associated pathways in primary fibroblasts.............. 20
3-4-1 EBV product-containing exosomes upregulate fibrosis-associated genes............. 20
3-5 EBV products-containing exosomes induce fibroblast activation.......................... 21
3-5-1 EBV products-containing exosomes promote activation of YAP1......................... 22
3-6
Exosome-stimulated fibroblasts enhance tumor growth and fibrotic response in
mouse xenografted tumor model............................................................................
22
3-7 Positive correlation between nuclear YAP1 and FAPexpression in NPC tumor samples................................................................................................................... 23
3-8 Cytotoxicity of YAP1 inhibitors in primary fibroblasts.......................................... 23
3-8-1 Inhibition of YAP1 blunts EBV products-containing exosome-mediated effects
on fibroblasts.......................................................................................................... 24
3-9 Blockade of YAP1 activity reduces fibroblast activation....................................... 24
Chapter 4 Conclusions and discussions................................................................................... 26
4-1 Exosomal content in EBV-related exosomes.......................................................... 26
4-2 The effects of EBV-related exosomes on other cell populations in the NPC TME 27
4-3 The impact of exosome-stimulated fibroblasts on the NPC TME.......................... 27
4-4 Exosome-mediated upregulation of other fibroblast activation markers................ 28
4-5 Future perspectives................................................................................................. 29
Chapter 5 Figures and Tables.................................................................................................. 30
Figure 1 IHC analyses of NPC tumor sections....................................................................... 30
Figure 2 Exosome visualization and uptake in primary fibroblasts....................................... 31
Figure 3 HK1EBV exosomes contains EBV-encoded LMP1................................................ 32
Figure 4 HK1EBV exosomes alter fibroblast morphology.................................................... 33
Figure 5 HK1EBV exosomes enhance cell contractility in fibroblasts.................................. 34
Figure 6 HK1EBV exosomes upregulate fibrosis-associated pathways in fibroblasts........... 35
Figure 7 HK1EBV exosomes upregulate genes involving in functions of fibrosis................ 36
Figure 8 HK1EBV exosomes enhance expression of fibrosis-associated genes.................... 37
Figure 9 HK1EBV exosomes induce fibroblast activation.................................................... 38
Figure 10 HK1EBV exosomes promote activation of YAP1................................................... 39
Figure 11 HK1EBV exosomes increase YAP1-targeted gene expression............................... 40
Figure 12 HK1EBV exosome-treated fibroblasts promote tumor growth............................... 41
Figure 13 YAP1 plays a critical role in exosome-mediated tissue remodeling........................ 42
Figure 14 IHC analysis of nuclear YAP1 and FAPexpression in NPC tumor sections......... 43
Figure 15 Determination of saracatinib cytotoxicity in fibroblasts.......................................... 44
Figure 16 Determination of verteporfin cytotoxicity in fibroblasts......................................... 45
Figure 17 Saracatinib suppresses HK1EBV exosome-mediated biological effects................. 46
Figure 18 Verteporfin diminishes HK1EBV exosome-mediated biological functions............ 47
Figure 19 Saracatinib reduces HK1EBV exosome-induced fibroblast activation................... 48
Figure 20 Verteporfin represses HK1EBV exosome-mediated fibroblast activation.............. 49
Figure 21 Proposed model of EBV products-containing exosomes-mediated fibroblast activation in NPC TME.......................................................................................... 50
Table 1 Primer information for QPCR analysis in primary fibroblasts................................. 51
References ................................................................................................................................ 52

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指導教授

劉淑貞(Shu-Chen Liu)

審核日期

2021-11-22

推文