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研究生： 應心瑜
Ying, Hsin-Yu
論文名稱： 通過物理壓力造成染色體不穩定進而調節免疫信號並促進胰臟癌進程
Chromosomal Instability via Physical Pressure Regulates Immune Signaling and Promotes Pancreatic Cancer Progression
指導教授： 黃柏憲
Huang, Po-Hsien
學位類別： 碩士
Master
系所名稱： 醫學院 - 生物化學暨分子生物學研究所
Department of Biochemistry and Molecular Biology
論文出版年： 2021
畢業學年度： 109
語文別： 英文
論文頁數： 46
中文關鍵詞： 胰腺癌 、Kras 、染色體不穩定 、基因異質性 、微核 、核膜 、物理壓力 、細胞遷移 、EMT 、cGAS
外文關鍵詞： Pancreatic cancer, Kras, Chromosomal instability, Gene heterogeneity, Micronuclei, Nuclear envelope, Physical pressure, Cell migration, EMT, cGAS
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    • 胰臟癌是世界上最致命的癌症之一，約95％的胰腺癌是胰腺導管腺癌（PDAC），其主要突變基因是KRAS。 PDAC內含有結構性的染色體不穩定性（Chromosomal instability），其中包含大量受損的DNA，並產生微核（MN），這種帶有脆弱核膜（Nuclear envelope）的異常細胞核區隔。通常，受損的DNA會在非癌細胞中引起免疫信號傳導，但此機制對癌細胞的作用尚不清楚。我們研究細胞於物理壓力下所產生的CIN，模擬體內細胞遷移，然後分析Kras胰腺癌細胞的免疫信號對cyclic GMP-AMP合成酶（cGAS）途徑和細胞腫瘤惡性程度已。首先，我們以來自小鼠（LSL-KrasG12D / +，Trp53 fl / fl，Pdx1-Cre）培養的原代細胞（P0）進行對3 µm微孔進行穿孔遷移來重複破壞NE，從而產生了穿越微孔移行之細胞株M1細胞至M3細胞。對比於小鼠腫瘤之序列活體移植腫瘤; P4 / P5細胞，是來自P0細胞的連續移植傳代細胞。免疫圖像顯示M3細胞中微核數量增加，並且微核中也積累了γH2AX，顯示其CIN的增加。 NE不穩定的核膜完整性，在M3細胞中是顯示不可逆的結果，表明破裂的NE是在物理壓力下產生的。 此外，M3細胞中細胞遷移能力的降低表明NE破裂的細胞在上皮-間質轉化上升，以western blot和qPCR也顯示出與EMT上升一致的結果。 在以M3癌細胞共條件培養基（conditioned medium）處理過的癌細胞中，pSTAT1和ß-半乳糖苷酶表現量降低，分別顯示cGAS途徑的反應降低和促進了Kras胰腺癌細胞的細胞生長。此外，我們在M3細胞和conditioned medium處理的細胞中觀察到對吉西他濱（Gemcitabine）和溴結構域(Bromodomain)抑製劑（JQ-1）的高耐藥性，這顯示了穿孔細胞透過CIN所獲得的耐藥性。總體而言，我們的數據支持癌細胞通過物理壓力擠壓去誘導CIN的產生去降低免疫信號活化並使細胞變的更惡性。

    Pancreatic cancer is the deadliest cancer in the world, 95% of pancreatic cancer type is pancreatic ductal adenocarcinoma (PDAC) that major mutant gene KRAS. PDAC shows a structural chromosomal instability (CIN) which contains a great amount of damaged DNA, this generate a micronucleus (MN) which is a mis-compartmentalization nucleus with a weak nuclear envelope (NE). Generally, damaged DNA will evoke immune signaling in non-cancer cells but these effects in cancer cells are unclear. We focus on CIN generation under physical pressure is mimic cell migration ex vivo then analyzed the immune signaling cyclic GMP-AMP synthase (cGAS) pathway and cell malignancy in Kras pancreatic cancer cells. First, we constructed M1 cells to M3 cells by repeating rupture their NE by trans-pore migration from the primary cell (P0) which is culture from well-characterized KPC (LSL-KrasG12D/+, Trp53 fl/fl, Pdx1-Cre) tumor of mice ; P4/P5 cell is a serial transplantation passage from a P0 cell. Immunofluorescent images showed increased number of MN in M3 cells and γH2AX was also accumulated in MN, which revealed increased CIN. NE integrity is unstable and isn’t reversible in M3 cells, Ruptured NE were generated under physical pressure. Decreased cell migration ability in M3 cells indicated NE ruptured cells undergo epithelial-mesenchymal transition (EMT). Western blot and qPCR data analytical these results. A low level of pSTAT1 and ß-galactosidase in M3 cells and conditioned medium (CM)-treated cells represent the cGAS pathway’s response was reduced and promoted cancer progression in Kras pancreatic cancer cells, respectively. Moreover, we observed a high drug resistance of gemcitabine (GEM) and bromodomain inhibitor (JQ-1) in M3 cells and CM-treated cells, which displayed a gains-of-function of drug resistance via CIN. Overall, our data supported cancer cells reduced immune signaling and gained malignancy via physical pressure induced CIN.

    摘要 I ABSTRACT II ACKNOWLEDGEMENT IV CONTENS V INTRODUCTION 1 AIMS 3 Aim1: Confirm Increasing MN numbers as a high malignant cells feature. 3 1-1. To define the base of the malignant cell on the survival curve between P0 and P4/P5 cells by IF. 3 1-2. To estimate MN’s amount in P0 and P4/P5 cells and define the malignant cells. 3 Aim2: Affirm MN are increased by trans-pore migration. 3 2-1. Culture migrated cells (M1, M2, and M3) with 3 µm transwell. 3 2-2. To estimate the ratio of MN numbers and nucleus deformation in migrated cells. 3 2-3. To estimate γ-H2AX levels in migrated cells. 3 Aim3: Investigate the NE integrity in trans-pore migrated cells. 3 3-1. To detect the NE integrity with IF image and simply divide cells into intact cells and non-intact cells. 3 3-2. To clarify the performance of NE’s single-section fluorescent distribution. 3 Aim4: Investigate the change of cellular morphology. 3 4-1. Observe the cellular morphology between these migrated cells and estimate the cells’ synapse length. 3 4-2. To estimate the cellular morphology under restricted-microenvironment (CM). 3 4-3. To estimate cell migration ability in migrated and CM-treated cells. 3 Aim5: Investigate Immune signaling expression, and verify the relationship between immune response and senescence in trans-pore migrated cells. 3 5-1. To detect immune signaling and malignant gene with WB and qPCR test. 3 5-2. To detect cellular senescence in migrated and CM-treated cells with ß-gal. 3 Aim6: Assume the high drug-resistance which cells gained via CIN. 3 MATERIALS AND METHODS 4 RESULTS 11 1. Increasing MN numbers observed in malignant cells. 11 2. MN are increased by trans-pore migration. 11 3. The NE integrity in trans-pore migrated cells 12 4. The migration ability after trans-pore migration was increased. 12 5. Immune signaling expression blocked in trans-pore migrated cells. 13 5-1. The relationship between immune response and senescence to regulate cancer progression. 14 6. Cells gain a drug resistance ability via CIN. 15 DISCUSSION 16 CONCLUSION 18 REFERENCES 19 FIGURES 24 Figure 1. Schematic depicting of KPC mice model and the comparison of MN numbers in P0 and P4/P5 cells. 25 Figure 2. Increasing MN are measure with the times of 3-µm filter migration and the NE intensity after trans-pore migration. 28 Figure 3. Kras mutated cells survive after passing through the 3-µm filter and the changes of cell synapse length after trans-pore migration. 30 Figure 4. Trans-pore migration cells increases the ability of migration in pancreatic cancer cells. 32 Figure 5. MN induction regulate the expression of, E-cadherin, vimentin and pSTAT1. 33 Figure 6. Expression peaks in the P0, M3, P4/P5, and CM-treated of mouse PDAC cells through RT-qPCR. 34 Figure 7. Induction of cellular senescence in mouse PDAC cells 35 Figure 8. Effects of gemcitabine and JQ-1 on mouse PDAC cell survival. 36 Figure 9. Schematic representation of cGAS-STING or TLR9 pathway via MN induction and NE rupture to regulate immune signaling. 37 Supplementary figure S1. Schematic depicting of MN location and the comparison of MN numbers in human pancreatic cancer cell lines. 38 Supplementary figure S2. The schematic representing of fragmented DNA nearby the chromosome. 39 Supplementary figure S3. Defined the optimal perforation trans-pore size of the NE for MN generation. 40 Supplementary figure S4. The cell survival and cellular morphology of Kras mutated cells both mouse and human after trans-pore migration. 41 TABLES 43

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