Our Thoughts (桀靜精微雷風相薄): 2015 MOST PPG

2015 MOST PPG

由 sufang 在五, 10/03/2014 - 13:18 發表

2015/05/29 口腔癌整合型計劃主題方向

Janelle Kuo <cckuo@nhri.org.tw>
AttachmentsMay 27 (2 days ago)
Reply
to Shih, 李岳倫, 陳雅雯, David, 林素芳
Chinese (Traditional)
English Translate message
Turn off for: Chinese (Traditional)
Dear all
這是今天討論的暫訂方向
先以這主題思索
也先寫上一個暫時性的題目
之後大家再努力想出更性感的題目吧
哈哈
珍

Su-Fang Lin <sflin1@gmail.com>
9:25 AM (4 hours ago)
Reply
to Janelle, Shih, 李岳倫, 陳雅雯, David
感謝靜娟精美的構圖!!

我上次認領的DNA methylation部分, 恐怕要釋出給別人了. 下面是各個相關基因對回去expression與methylation array的結果:
1. TDO2 [1.3.11.11] expression T/N 10X, methylation q > 0.3
2. IDO1 [1.3.11.52] expression T/N 3.4X, methylation q > 0.3
3. KYNU [3.7.1.3] expression T/N 1.9X, methylation -0.3574
4. KMO [1.14.13.9] expression T/N 1.6X, methylation -0.2511
5. AADAT [1.14.13.9] expression T/N 0.8X, methylation -0.4187
6. ALDH3A2 [1.2.1.3] expression T/N 0.58X, methylation q > 0.3
7. ALDH1B1 [1.2.1.3] expression T/N 2X, methylation q > 0.3
8. IL4I1 [1.4.3.2] expression T/N 4.7X, methylation q > 0.3
9. EHHADH [4.2.1.17] expression T/N 1.8X, methylation q > 0.3
10. MAOB [1.4.3.4] expression T/N 0.4X, methylation q > 0.3
11. AOX1 [1.2.3.1]] expression T/N 0.5X, methylation q > 0.3
12. INMT [1.49 2.1.1.96] expression T/N 0.5X, methylation q > 0.3

看起來唯有#5 AADAT微微的和hyper-methylation有關. 殘念. SF

Start: 10/03/2014

Timezone: Asia/Taipei

Bookmark/Search this post with


	#1由 sufang 在五, 05/29/2015 - 13:49 發表。 2015/05/15 新方向 2015/05/15 新方向 -> metabolism Janelle Kuo <cckuo@nhri.org.tw> May 15 Dear all 回應小雯如果以pan ca 的計畫為例先不管個人的 interested 他們 focusing 的主軸為 K-Ras driven 探討的 metabolism effect 包含：常醫師：glycolysis 鄭光宏：metabolic shift (看題目不知他focus的 metabolic pathway，有可能是先screening) 莊老師：glycolysis 小黑：lipid metabolism 韋恩：tumor-stromal metabolomics (看題目不知他focus的pathway，有可能是先screening) 綜此，他們為glycolysis and lipid metabolism 加上先前陳所長的ADI 所以 Pan ca group 在 metabolism 的方向包括 (1) glycolysis、(2) lipid metabolism、(3) amino acid metabolism (focusing on arginine) 我們oral cancer team 目前 Alan focusing on amino acid metabolism (proline、glutamine) 我的EGFR reprogram study 是focusing on glycolysis、另外也有在看 glutamine 代謝綜此在此部份我們有的基礎為 (1) glycolysis (2) amino acid metabolism (proline、glutamine) 以上珍刪除編輯回應


	#2由 sufang 在一, 05/18/2015 - 09:57 發表。 2015/05/08 email 紀錄 Re: 口腔癌整合型計劃主題討論outline (by 珍)_2015.05.08 Ya-Wen Chen <980727@nhri.org.tw> Attachments May 13 For your references. Best, Ya-Wen Janelle Kuo <cckuo@nhri.org.tw> May 13 謝謝小雯珍 Su-Fang Lin <sflin1@gmail.com> May 14 (4 days ago) Reply to Ya-Wen, Janelle, 李岳倫, David, Shih 謝謝雅雯提供的figure! Accordingly, I listed all the genes involved in one-carbon metabolism as follows, except "ALDH2" which I found in this reference. AHCY ALDH1L1 ALDH2 AMT ATIC BHMT DHFR DNMT1 DNMT3A DNMT3B FOLH1 FTCD GART KIAA0828 MAT1A MAT2B MTFMT MTHFD1 MTHFD1L MTHFD2 MTHFR MTHFS MTR MTRR SHMT1 SHMT2 TCNII TYMS 長長的、有點醜, 不過希望將子Johnson只要copy/paste就可以放在excel檔使用 Best, Su-Fang ************************** 口腔癌整合型計劃主題_2015.05.14 Janelle Kuo <cckuo@nhri.org.tw> May 14 to 李岳倫, 陳雅雯, David, 林素芳, Shih Dear all 今天下午我的 Lab meeting，我和欣蕙 (我的 postdoc，負責 MTHFD2 study) 說，先前規劃 MTHFD2 要提個人型的科技部計畫，現要改成PPG，因為其他老師也有興趣，想要一起參與。我把我們昨天討論的規劃和實驗室的同仁說明，欣蕙說她目前有幾個方向 (arecoline effect、cell cycle and DNA synthesis、mitochondria activity、EMT、與metastasis)，都在進行與確認中，如果要現在馬上選擇只朝一個方向進行，她覺得有困難，希望再給她幾個月的時間，以確認後續要深入進行的方向。接著，實驗室的助理說，老師妳現在要欣蕙做決定，有些太為難她了，因為她這一年來都在做這 project，忽然很多人一起來看，然後要她馬上決定只能朝一個方向進行，她很為難，也沒有安全感，畢竟她花了很多的心血了。所以，我要和大家道歉，我疏忽了實驗室同仁的想法，他們很努力工作，但老闆沒有想到他們也有需求。所以我想，現階段有關 MTHFD2 的研究，還是按原先的規劃，申請科技部個人型計畫。待欣蕙進行一陣子累積更多的基礎後，如果未來大家還有興趣，我們再來架構整合的方向。所以，傍晚我很不好意思的下樓來，也和Alan 說明了這狀況。Alan 說我們的 PPG 可以還是以 cancer metabolism 為主來串連，如 proline、glutamine 的代謝也都很重要。所以我們是否先以 cancer metabolism 為主軸，大家去想昨天的討論：(1) EMT/metastasis (雅雯)、(2) mitochondria/DNA replication/EMT/angiogenesis/metastasis (Alan)、(3) Immunomodulation (Johnson)、(4) miRNA (興國)、(5) arecoline effect (素芳)，可以如何下手去串連。至於我的部份，我可能會朝 chemoresistance 或 therapeutic approach 去看，也可以併在任一個子計畫中。不好意思，麻煩大家了。珍____________________________ Ya-Wen Chen <980727@nhri.org.tw> May 14 我可以理解, 沒關係啦. 題目再找就有了, 我們可是強大的口腔癌團隊. 也謝謝珍奈兒讓我這門外漢開始有機會準備要參與這hot topic. 不過, 是不是可以請已經入門的人, 再提供一些可能的pathways? Best, Ya-Wen 刪除編輯回應


	#3由 sufang 在一, 05/18/2015 - 09:43 發表。 2015/05/07 開會紀錄口腔癌整合型計劃主題討論outline (by 珍)_2015.05.07 to Alan Yueh-Luen., Ya-Wen, David, 林素芳, Shih, 林佩瑩 Dear all 很開心在星期三下午，和大家有很熱烈的討論，由於部份好友陸續趕車，所以最後剩Alan、小雯、和我繼續討論，並根據大家的想法，以及目前研究的「熱點」，暫時歸納出可能的兩個主題 (我們PPG要探索與擬解決的問題)，期盼大家繼續腦力激盪，以產生更多的火花： (1) Immunomodulation and therapy：因為目前很夯，且我們的array data 很漂亮，因此，在此部份有很多可以著墨的空間，且這樣的主題也較有機會受到審查委員的青睞。 (2) Recurrence：了解 recurrence 的原因與解決相關的問題，這部份也是相當重要的議題，且 recurrence 與 metastasis、microenvironment (含immune factors)、therapeutic resistance 也都有關，可據此進行探討並找尋可對應的診斷標記與治療策略。但這部份我們必須要想出一個可串連彼此的主題。另外，還有一個今天和 Johnson 討論我的 data 時，衍生的主題。大家都知道我最近對一個 folate/one carbon metabolism 的酵素 MTHFD2 很感興趣，也累積了一些 data。今天我和 Johnson 講這個故事，並請 Johnson 從他的觀點給予意見。Johnson 藉由 Oncomine 的搜尋，發現 MTHFD2 與很多重要的 oncogenic factors co-expression (包括 glycolysis、EMT、metastasis、cell cycle、DNA repair、purine/pyrimidine synthesis 等調節因子, etc.)，且在很多的 dataset 都與 clinical outcome 有關。我原先是想提個人型的科技部計畫，但 Johnson 覺得這個題目可以結合大家的專長去做，並串連素芳之前提出的 folate dysregulation 與 hypermethylation 的 idea，作為另外一個 PPG 題目的選擇。所以是否 folate/one carbon metabolism 可以作為我們繼 “retinoic pathway” 之後的另一個擬開拓的疆土，我們也可以再集思廣益。以上，只是小妹我小小的outline，若有沒交代清楚的，再請各位大大補充與 input 您們的想法。目前 Alan 將會在本月再規劃 2 次腦力激盪大會，希望在6月2日下台南前，我們可以擬出一個具體的方向。若有任何想法，大家也可以在email 中持續討論。我們一定要成功！必勝！必勝！必勝！珍珍 ---------- Ya-Wen Chen Dear all Thanks for Janelle's summary and great ideas from everyone. 請問MTHDFD2與immunomodulaton或recurrence是否有關啊? Best, ------------------ Su-Fang Lin 謝謝珍奈兒! 抱歉每次都因趕車要先離席.. 還有, 杯子我取回了謝謝雅雯!! SF --------------------------- David Shiah 謝謝靜娟：同時很抱歉應為要趕短程交通車，提早離席!! 靜娟的整理非常詳細，我個人對於 MTHFD2 相關的部分很有興趣 (其次是recurrence的部分)，因為 MTHFD2 可以連結一個完整的"代謝"路徑，又跟hypermethylation及臨床outcomes有關，我這邊就有可以切入的點，相關的訊息，下次再跟大家報告!! 興國 --------------------- Janelle Kuo Dear all MTHFD2 和recurence和clinical outcome有關在immune中的角色未知可以等Johnoson分析的結果再和大家開獎囉 Best 珍 ---------------- Ya-Wen Chen May 8 (1 day ago) MTHDFD1?又是如何? Best, ------------- Dear 小雯請參考下圖資料三個在mitochondria 紅字的酵素在40對也都up (MTHFD2 與MTHFD1L pattern 尤像) 這個路徑也會link to glycine 與serine 的合成目前也有一派的理論認為glycine、serine 的合成對cancer metabolism 而言是 more important than glycolysis Best 珍 ---------------- Ya-Wen Chen Thanks Janelle~ MTHDFD1?沒有表現嗎? 嘻..代謝生化好像有點陌生(我...還是生化所畢業的咧??) Best, ------------------ Janelle Kuo MTHFD1 也是up的阿但是它在cyotosol 不是在mitochondria裡面要把範圍擴大或 focus 在mitochondria 大家可以再討論喔珍 ***************** Dear all: 感謝珍的整理記錄，相信大家已有初步的構思了。也謝謝珍提出MTHFD2 相關主題，至於是否與immunomodulaton或recurrence/metastasis是否有關，就請大家多方收集資料，也可在下次討論。接下來的聚會討論，我規畫在6/2 赴台南前再討論兩次，之後將初步決定的方向主題與蕭醫師交換意見，是否符合臨床角度之可行性與實用迫切性，可供我們之後修正的考量。主題的選定及高度相當重要，決定計畫成功的機率。在主題選定後，才可邀請相關的合作成員，當然，其他成員資源的來源與充沛與否也是主題選定的考量之一。依舊，就請大家標出不行的時間，然後我再統整時間。這次希望能有較充裕的時間討論，就請大家提早預留時間。若有任何建議或遺漏歡迎提醒預祝成功 Thanks Alan *************** Janelle Kuo <cckuo@nhri.org.tw> Reply to 李岳倫, 陳雅雯, David, 林素芳, Shih, 林佩瑩 Dear all 有關 MTHFD2 的 idea，在 4/24 我有報給龔院長聽，他也覺得很 impressive，4/30也有在台北和他再私下討論這個議題。因為當初是想提個人型計畫，希望他能協助我 metabolic panel screening 的部份，他有允諾可以幫忙。所以如果我們確定要以這主題提PPG計畫，禮貌上我需要和他報告一下這個狀況，我想他也會支持我們的。另外，MTHFD2有兩個好朋友，MTHFD1L 與 SHMT2 角色也很重要，在我們 array data up也很顯著。看我們是要 narrow down 到一個基因，還是以 folate/one carbon metabolism 為主進行思考，希望大家一起集思廣益。當然，若有其他更好的題目，我們就往更好的方向走，我們要努力成為台灣最棒的口腔癌研究團隊！我可以的時間如下表 Best 珍珍 *************** 刪除編輯回應


	#4由 sufang 在一, 01/12/2015 - 16:21 發表。 Small containers, important cargo Small containers, important cargo http://www.nature.com/nrc/journal/v14/n12/full/nrc3864.html M. Teresa Villanueva Nature Reviews Cancer 14, 764–765 (2014) doi:10.1038/nrc3864 Published online 24 November 2014 The role of exosomes as mediators between cancer cells and the microenvironment has gained increasing attention. Two studies have provided further information on the part these small vesicles play in tumour progression and resistance to therapy. Lara Crow / NPG Boelens et al. were interested in how stromal communication with cancer cells can influence treatment response. The authors had previously characterized a gene signature for radiation resistance that included many interferon-stimulated genes (ISGs), termed the interferon-related DNA damage resistance signature (IRDS). As ISGs can be regulated by the microenvironment, the authors examined ISG expression in xenografts derived from the metastatic breast cancer cell line MDA-MB-231 alone or co-injected with fibroblasts. Tumours containing both cancer cells and fibroblasts showed high expression of several IRDS genes, including STAT1, and maintained proliferation after radiation treatment, whereas tumours from breast cancer cells alone had lower IRDS expression and regressed after radiation treatment. The authors also identified two groups of breast cancer cells: IRDS responders (IRDS-Rs) — in which interaction with fibroblasts induced IRDS genes and conferred protection against radiation (mediated by STAT1) — and IRDS non-responders (IRDS-NRs), in which interaction with fibroblasts failed to induce IRDS or protect against radiation. Through computational analysis, the pattern recognition receptor RIG-I was identified as the mediator of fibroblast-induced upregulation of STAT1 and IRDS genes. Indeed, knocking down RIG-I in IRDS-Rs inhibited IRDS gene induction and radiation protection in cancer cells after co-culture with fibroblasts. Conditioned media from IRDS-Rs cultured with fibroblasts upregulated IRDS genes in breast cancer cells, suggesting the presence of a secreted factor that is capable of activating RIG-I in these cells. The authors found that this paracrine induction of IRDS genes was triggered by an increase in the number of exosomes after co-culture, which were transferred from stromal cells to breast cancer cells. Further experiments showed that these exosomes contained 5′-triphosphate RNA that can activate RIG-I signalling in breast cancer cells. Breast cancer cells separated from fibroblasts by a transwell filter that allowed exosome transfer retained IRDS induction but lost resistance to radiation, suggesting that RIG-I mediates radiation resistance in a juxtacrine way. A computational analysis of the interactome between IRDS-Rs and fibroblasts revealed that expression of NOTCH3 was increased in IRDS-Rs, and its membrane-bound ligand JAG1 was induced in fibroblasts. The authors found that STAT1 (which mediates fibroblast-induced expression of IRDS genes in cancer cells) was required for the transcription of NOTCH3 and NOTCH target genes. Inhibition of the NOTCH pathway with a γ-secretase inhibitor after radiotherapy reversed the protection conferred by fibroblasts and eliminated xenograft tumours in 30% of mice. So, stromal exosomes transfer 5′-triphosphate RNA to mediate activation of RIG-I signalling in breast cancer cells, which then — through STAT1 — cooperates with NOTCH3 to expand radiation-resistant cells. Melo et al. investigated the contribution of microRNAs (miRNAs) contained in exosomes to tumour progression. The authors analysed exosomes secreted by breast cancer cell lines (such as MDA-MB-231) and by non-tumorigenic human mammary epithelial cells (MCF10A cells), and observed that six miRNAs, all of which have been widely implicated in cancer progression, were increased in cancer exosomes. Incubating purified exosomes for different periods of time showed an enrichment of miRNAs over time, suggesting active miRNA biogenesis in exosomes. Further analysis revealed the presence of pre-miRNA, as well as the required proteins to process them (the key components of the RISC-loading complex). Incubation of MCF10A cells with MDA-MB-231-derived exosomes induced oncogenic transcriptome changes in MCF10A cells, and MCF10A cells exposed to cancer exosomes could then form tumours when implanted into nude mice. Moreover, exosomes isolated from the serum of patients with breast cancer also induced MCF10A cell tumorigenesis, whereas exosomes from healthy donors did not. “exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression” These two papers describe how exosomes can alter the transcriptomes of target cells to promote therapeutic resistance, as well as tumour initiation and progression, opening new possibilities for developing exosome-based biomarkers and therapies. References Boelens, M. C. et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell 159, 499–513 (2014) CASArticle Melo, S. A. et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26, 707–721 (2014) 刪除編輯回應


	#5由 sufang 在六, 01/10/2015 - 10:41 發表。 Extracellular vesicles as carriers of microRNA, proteins and lip Int J Cancer. 2015 Jan 5. doi: 10.1002/ijc.29417. [Epub ahead of print] Extracellular vesicles as carriers of microRNA, proteins and lipids in tumor microenvironment. pdf 4268 http://www.ncbi.nlm.nih.gov/pubmed/25559768 Penfornis P1, Vallabhaneni K, Whitt J, Pochampally R. Author information Abstract In recent years the knowledge about the control of tumor microenvironment has increased and emerged as an important player in tumorigenesis. The role of normal stromal cells in the tumor initiation and progression has brought our vision in to the forefront of cell-to-cell communication. In this review, we focus on the mechanism of communication between stromal and tumor cells, which is based on the exchange of extracellular vesicles. We describe several, ever-growing, pieces of evidence that extracellular vesicles transfer messages through their miRNA, lipid, protein and nucleic acid contents. A better understanding of this sophisticated method of communication between normal cancer cells may lead to developing novel approaches for personalized diagnostics and therapeutics. This article is protected by copyright. All rights reserved. © 2015 UICC. PMID: 25559768 刪除編輯回應


	#6由 sufang 在六, 01/10/2015 - 10:28 發表。陽明大學-臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密陽明大學-臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密由 sufang 在三, 12/31/2014 - 12:54 發表 Oral Cancer oral cancer news 103年12月10日楊慕華教授記者會【陽明大學-臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密】傳統的癌症治療通常是以癌細胞做為治療的首要標的，例如化學治療是根據癌細胞快速增殖的特性，以化學藥物抑制癌細胞的增生；大部分的標靶治療，是針對癌細胞表現的特殊分子進行阻斷治療。但惡性腫瘤的組成，是包括種子(癌細胞)與土壤(宿主細胞)兩大部分，亦即除了癌細胞外，尚需許多其他種類的細胞共同形成腫瘤，這些細胞包括宿主的免疫細胞，血管內皮細胞，纖維母細胞等等，此即腫瘤生物學中重要的“種子與土壤”理論。因此，腫瘤細胞能躲過患者免疫系統監控持續生長，甚至重塑腫瘤微環境，使宿主細胞由“敵人”變為有利於腫瘤細胞的“戰友”，是腫瘤惡化的關鍵。近年癌症醫學快速進展，腫瘤免疫學已成為最熱門的研究課題，許多治療也因應而生。但是腫瘤轉移時，這些惡性度更高的“變形”癌細胞，如何反客為主，改造腫瘤微環境，仍多有未知。但最近，陽明大學-臺北榮總的腫瘤免疫團隊，有了新的突破性的發現！由陽明大學臨床醫學研究所楊慕華教授領導的癌症研究團隊，在與免疫學專家-陽明大學微生物免疫學研究所陳念榮副教授，以及頭頸癌專家-臺北榮總耳鼻喉頭頸部戴世光教授合作下，發現了頭頸癌惡化時，會分泌各種細胞激素，誘使宿主巨噬細胞聚集至腫瘤處，並“改造”這些免疫細胞成為癌症的幫兇，加速腫瘤的惡化與轉移。這項重要發現，已於今年十月十三日在癌症醫學界具領導地位的頂尖期刊“癌細胞”(Cancer Cell)發表。楊教授的團隊過去在頭頸癌轉移研究有相當豐富的經驗，先前的系列研究已發現轉移調控蛋白Snail在誘發癌症幹細胞生成，增加細胞侵犯性扮演關鍵性角色。本研究楊教授團隊基於過去研究成果，進一步探討Snail如何重塑腫瘤微環境。研究團隊發現，當腫瘤處於一種輕微發炎狀態時，腫瘤壞死因子(tumor necrosis factor a；TNFa)可促進Snail的乙醯化(acetylation)，而這個訊號乃是誘發腫瘤微環境重塑的關鍵。乙醯化的Snail具有誘發各式細胞激素的能力，進一步吸引宿主巨噬細胞(macrophages)於腫瘤處聚集。巨噬細胞原本是具有吞噬外來病原的免疫細胞，但腫瘤處聚集的巨噬細胞，經癌細胞的影響後，反而促進腫瘤之血管新生與惡化。楊教授進一步與陳念榮副教授合作，使用TNFa基因剔除鼠進行動物實驗，發現腫瘤分泌的TNFa是操控這個惡性循環的元凶。研究團隊也分析頭頸癌的病患標本，發現乙醯化Snail確實與腫瘤組織中巨噬細胞的數量有關：腫瘤細胞中表現較多的乙醯化Snail，通常伴隨較大量的巨噬細胞聚集，而此類病患的預後也較差。圖一顯示小鼠實驗結果：在TNFa基因剔除鼠植入表現Snail之癌細胞，若抑制癌細胞中之TNFa表現，腫瘤轉移與巨噬細胞聚集均會減少。圖二為頭頸癌組織標本，case 1為有較高乙醯化Snail表現之病例，腫瘤處也聚集較多之巨噬細胞；case 2則是乙醯化Snail低表現之個案，腫瘤處巨噬細胞也較少。圖一在TNFa基因剔除鼠植入表現Snail之癌細胞(LLC1-Snail)或是表現Snail但抑制TNFa之癌細胞(LLC1-Snail-shTNFa)。上圖為小鼠肺部，箭頭指出處為轉移腫瘤；下突為植入腫瘤組織切片，紅色染色處為巨噬細胞。圖二頭頸癌病患腫瘤組織中乙醯化Snail(左圖箭頭標示處之紅點)與巨噬細胞(右圖棕染色處)。本研究最具意義的是發現了腫瘤惡化過程中，癌細胞透過TNFa誘發Snail乙醯化為腫瘤微環境重塑之關鍵，未來若能針對此訊號做為阻斷標的，將對晚期癌症治療產生重要影響。本研究特色是跨領域臨床與基礎醫學合作：楊慕華教授是癌症生物學的專家，也同時是腫瘤專科醫師，多年來專注於腫瘤轉移的分子生物學研究；陳念榮副教授是免疫學專家，對於巨噬細胞有相當深入的研究；臺北榮總戴世光教授為頭頸外科醫師，是頭頸癌治療的專家。論文第一作者許信賢博士是陽明大學臨床醫學研究所的博士後研究員，長期在楊教授指導下進行癌症轉移研究，著手進行本研究已有三年半之久。其餘團隊成員均為楊教授實驗室成員，包括研究助理王曉蓉小姐，博士生周俊宏先生，博士生謝佳欣小姐，以及研究助理邱柏憲先生。本研究完全於台灣進行，整個研究都在陽明大學及臺北榮總內完成。楊教授的研究團隊，近年在癌症研究上有豐碩的研究成果，除本論文外，團隊已於四年內三度在頂尖細胞生物學期刊Nature Cell Biology發表研究成果，且均為於本土進行的腫瘤轉移之系列研究，使本團隊成為癌症轉移研究之國際一流團隊。楊教授本身為醫師科學家，同時肩負科學研究與臨床癌症醫療的任務，所有基礎與臨床醫學訓練均在陽明大學與台北榮總完成。楊教授近年的研究成果，顯示純本土訓練培養的研究團隊，已達國際一流水準，尤其是在國人重要疾病頭頸癌研究上居於領先地位，對本土醫師科學家以及生物醫學研究者，具有相當大之意義。刪除編輯回應


	#7由 sufang 在四, 11/20/2014 - 12:58 發表。 Preconditioning the ECM for fibrosis Preconditioning the ECM for fibrosis Nature Reviews Molecular Cell Biology \| Research Highlight Published online 12 November 2014 Remodelling of the extracellular matrix (ECM) by myofibroblasts is crucial for wound repair, but if dysregulated can result in pathological fibrosis. Hinz and colleagues describe how pre-organization of the ECM by myofibroblasts can prime for increased fibrosis by regulating the activation of the pro-fibrotic cytokine transforming growth factor-β (TGFβ). Latent TGFβ is secreted bound to latency-associated peptide (LAP), which binds to the ECM protein latent TGFβ-binding protein 1 (LTBP1). Integrin-dependent binding of contracting myofibroblasts to LAP induces a conformational change in LAP that releases active TGFβ from the ECM. Therefore, the short-term contractile state of the wound determines the activity of TGFβ. New work now shows that this process is augmented by longer-term changes to the organization of the ECM. “differences in ECM structure might affect contraction-induced TGFβ1 activation” In a rat model of wound healing, restraining the wound edges mechanically resulted in accelerated expression of ECM proteins such as fibronectin and LTBP1, and increased fibril organization of the ECM, which correlated with increased TGFβ1 signalling. This increased ECM organization was the result of increased strain exerted by myofibroblasts. High-contractile human dermal myofibroblasts (DMFs) had increased expression of ECM proteins compared with low-contractile human dermal fibroblasts (DFs), and there was greater organization of LTBP1 and fibronectin in the DMF ECM than in the DF ECM. Moreover, cell contraction resulted in threefold higher levels of active TGFβ1 in human DMF cultures compared with human DF cultures. This indicates that differences in ECM structure might affect contraction-induced TGFβ1 activation. In support of this, when decellularized ECM from human DMFs and from human DFs was reseeded with human DMFs, DMF contraction-induced activation of TGFβ1 was twofold greater from DMF-remodelled ECM than from DF-remodelled ECM, despite similar total levels of TGFβ1. This correlated with the extent of ECM organization, which was significantly higher in DMF cultures than in DF cultures. The authors confirmed that pre-organization of the ECM affects TGFβ1 activation using Fak−/− mouse embryonic fibroblasts, which have a disorganized ECM with a low fibril density and are defective for TGFβ activation. Increasing the pre-strain of the ECM using a mechanical strain device — to rapidly simulate long-term ECM straining by myofibroblasts — correlated with increased levels of TGFβ1 activation by human DMF contraction. Furthermore, at high levels of ECM pre-strain, TGFβ could be activated in the absence of human DMFs, and the strain threshold for this was lower for DMF ECM than for DF ECM, which is in keeping with the greater level of organization of the DMF ECM. The results suggest that mechanical pre-straining of the ECM determines the efficacy of TGFβ activation, which sets a mechanical threshold for the pro-fibrotic activity of myofibroblasts. Manipulating this threshold could have important implications for normal versus fibrotic tissue repair. References Klingberg, F. et al. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201402006 (2014) J Cell Biol. 2014 Oct 27;207(2):283-97. doi: 10.1083/jcb.201402006. Epub 2014 Oct 20. Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation. pdf:4270 PMID: 25332161 Klingberg F1, Chow ML1, Koehler A1, Boo S1, Buscemi L2, Quinn TM3, Costell M4, Alman BA5, Genot E6, Hinz B7. Author information Abstract Integrin-mediated force application induces a conformational change in latent TGF-β1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical activation of TGF-β1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-β1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-β1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-β1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer. 刪除編輯回應


	#8由 sufang 在四, 10/09/2014 - 16:38 發表。 The polyphenol EGCG and luteolin inhibits TGFb induced myoblast PLoS One. 2014 Oct 1;9(10):e109208. doi: 10.1371/journal.pone.0109208. eCollection 2014. The Polyphenols (-)-Epigallocatechin-3-Gallate and Luteolin Synergistically Inhibit TGF-β-Induced Myofibroblast Phenotypes through RhoA and ERK Inhibition. Gray AL, Stephens CA, Bigelow RL, Coleman DT, Cardelli JA. Author information Abstract The presence of reactive stroma, predominantly composed of myofibroblasts, is directly associated with and drives prostate cancer progression. We have previously shown that (-)-Epigallocatechin-3-gallate (EGCG), in the form of Polyphenon E, significantly decreases serum levels of HGF and VEGF in prostate cancer patients. Given that HGF and VEGF are secreted from surrounding tumor myofibroblasts, these observations suggested that EGCG may inhibit prostate cancer-associated myofibroblast differentiation. Herein, we demonstrate that micromolar combinations of EGCG and a second polyphenol, luteolin, synergistically inhibit TGF-β-induced myofibroblast phenotypes in prostate fibroblast cell lines, as observed primarily by potentiation of fibronectin expression. Functionally, EGCG and luteolin inhibited TGF-β-induced extracellular matrix contraction, an enhancer of tumor cell invasion. EGCG and luteolin inhibited downstream TGF-β-induced signaling, including activation of ERK and AKT, respectively, but mechanistically, only ERK appeared to be necessary for TGF-β-induced fibronectin expression. Furthermore, neither EGCG nor luteolin affected Smad signaling or nuclear translocation. Rho signaling was found to be necessary for TGF-β-induced fibronectin expression and EGCG and luteolin each reduced RhoA activation. Finally, EGCG and luteolin were shown to reverse TGF-β-induced fibronectin expression, implicating that these natural compounds may be useful not only in preventing but also in treating already activated myofibroblasts and the diseases they cause, including cancer. The ability of EGCG and luteolin to synergistically target myofibroblasts suggests that combined clinical use of these compounds could prevent or reverse cancer progression through targeting the tumor microenvironment, in addition to the tumor itself. PMID: 25272043 刪除編輯回應


	#9由 sufang 在四, 10/09/2014 - 16:33 發表。 ECM stiffness paves the way for tumor cells Nature Medicine 20, 332–333 (2014) doi:10.1038/nm.3523 Published online 07 April 2014 In the mammary gland, the stiffness of extracellular matrix (ECM) collagen is thought to influence tumor progression and clinical outcome. A new mechanism orchestrated by a microRNA circuit is shown to mediate the physical effects of the microenvironment on tumor cell progression. The findings may explain how increased breast matrix stiffness is associated with poor survival and could help identify women with aggressive breast cancer (pages 360–367). Increased ECM stiffness promotes β1 integrin clustering, transcriptionally activates MYC and induces the polycistronic miR-17-92 cluster. This results in the upregulation of a particular miRNA, miR-18a, which, in turn, reduces expression of PTEN and HOXA9. Low PTEN increases signaling through the phosphoinositide 3-kinase (PIP3)–AKT pathway, promoting invasion and metastasis. Increased ECM-generated mechanical force can therefore regulate the expression of PTEN, HOXA9 and also BRCA1 via a miR-18a–dependent signaling network. FAK, focal adhesion kinase; IP3, inositol triphosphate. 刪除編輯回應

#10由 sufang 在四, 10/09/2014 - 10:00 發表。

Fwd: 萊富蕙敏~~TO:劉柯俊老師

劉柯俊
Sep 24 to 夏興國, 林素芳, 劉柯俊

開始轉寄郵件：

> 寄件人: "Wang, Laetitia" <Laetitia.Wang@thermofisher.com>
> 標題: 萊富蕙敏~~TO:劉柯俊老師
> 日期: 2014年5月6日 GMT+8上午10時18分19秒
> 收件人: "kojiunn@nhri.org.tw" <kojiunn@nhri.org.tw>
>
> 老師:
>
> "Total Exosome RNA and Protein Isolation Kit"是純化protein RNA的kit
>
>
> 而抽EXSOME的有分:
>
> Total Exosome Isolation (from serum) 貨號:4478360
>
> Total Exosome Isolation (from cell culture media) 貨號:4478359
>
> Total Exosome Isolation (from other body fluids) 貨號:4484453
>
> Total Exosome Isolation (from urine) 貨號:4484452
>
>
>
> 大約PROTOCOL:
>
> http://tools.lifetechnologies.com/content/sfs/manuals/total_exosome_plas...
>
> 就是高速離心這樣~~~
>
> Laetitia
> Sales 王蕙敏
>
> T (07) 226 1886*708 ‧ M 0978305362‧ F (07) 223 7640
> 7F.-1, No.20, Zhongzheng 2nd RD., Lingya Dist., Kaohsiung City 80271, Taiwan R.O.C
>
> 賽默飛世爾科技 Thermo Fisher Scientific

#2由 sufang 在六, 01/10/2015 - 10:22 發表。 2014/09/18 – 09/29 (上車與下車的回憶) 2014/09/18 – 09/29 (上車與下車的回憶) Janelle Kuo Sep 18 to Dr. 劉滄梧, Dr. 江士昇, Dr. 張書銘, Dr. 陳雅雯, Dr. 李岳倫, me, Dr. 夏興國 Dear all 根據今天下午討論的整合型計畫構想現階段進度如下總計畫名稱：Identification of potential biomarkers for the carcinogenesis and progression of oral cancer (暫定，需再提出更sexy的題目) 總計畫主持人：劉滄梧 (1) 子計畫一：Cancer metabolism and Immune factor 主持人：劉滄梧共同主持人：江士昇、郭靜娟、(劉柯俊 to be confirm) (2) 子計畫二：SNP and prognosis 主持人：張書銘共同主持人：蕭振仁 (3) 子計畫三：Genome instability and LOHmarker 主持人：陳雅雯共同主持人：李岳倫 (4) 子計畫四：Folate and methylation 主持人：林素芳 (5) 子計畫五：Carcinogenesis associated miRNA 主持人：夏興國請大家星期一先交以下資料以供總計畫內容彙整之用 1. 建議的總計畫名稱 (含中、英文) 2. 各子計畫名稱 (含中、英文)、摘要 (中文)、預期目標 (中文) 附加檔案為構想書格式、審查意見表、以及整合型計畫範本 (此為密件、請勿轉寄) Good luck for us Best wishes JJ ---------------------------- Janelle Kuo Sep 18 to Dr. 劉滄梧, Dr. 江士昇, Dr. 張書銘, Dr. 陳雅雯, Dr. 李岳倫, me, Dr. 夏興國 Dear all 星期一除了繳交 title/ abstract/ specific aims 也煩請針對各子計畫主題提出自己負責的子計畫與其他子計畫之關係，包括整合性與互補性也請簡略說明計畫之原創性及學術或應用上之價值拜託囉謝謝 JJ ------------------------- Ya-Wen Chen Sep 19 to Janelle, Dr. 劉滄梧, Dr. 江士昇, Dr. 張書銘, Dr. 李岳倫, me, Dr. 夏興國收到.要趕的作業還不少. Best, ------------------------ 張書銘 Sep 21 to 陳雅雯, 李岳倫, hsiaojr, 郭靜娟, 劉滄梧, Shih, me, Shine-Gwo Dear all: Here is my LOI. I welcome your comments and suggestions. Best wishes, Jeffrey ------------------------ Su-Fang Lin <sflin1@gmail.com> Sep 21 to 張書銘你也太厲害了吧! 好，素芳加油~ ------------------------ David Shiah Sep 23 to 張書銘, 郭靜娟, 劉滄梧, Shih, 陳雅雯, 李岳倫, me, Shine-Gwo, hsiaojr Dear all：我這部分子計畫的LOI草稿也寫好了，先給大家參考，內容會再部分修改(子計畫間關聯部分)，謝謝!! Best, 夏興國 ------------------------ Ya-Wen Chen Sep 23 to David, 張書銘, 郭靜娟, 劉滄梧, Shih, 李岳倫, me, Shine-Gwo, hsiaojr 哇~我還沒寫.... ------------------------ Janelle Kuo Sep 23 to David, 張書銘, 劉滄梧, Shih, 陳雅雯, 李岳倫, me, Shine-Gwo, hsiaojr Dear 興國 Got it. Thanks and have a nice trip. Best Janelle ------------------------ Su-Fang Lin <sflin1@gmail.com> Sep 23 to Ya-Wen, David, 張書銘, 郭靜娟, 劉滄梧, Shih, 李岳倫, Shine-Gwo, 蕭振仁醫師我想好了，但也還沒動手，所以雅雯我陪妳->搞完缺口再來拼這裡。Yet... 上週三傍晚開會中獅子所長提了一個寫整合型計劃的idea: microbiota 與 tissue microenvironment (pdf 4143 TME, Weinberg大師是這麼縮寫的應該流行得下去 (嗚嗚可憐的「口潛惡症」...) )。我在想大家的東西是不是都可以扯到TME而把總標題定為 Tissue Microenvironment of Oral Cancer. 然後像Jeffery新的題目當然沒問題可以fit進去TME，興國的只要多加一步exosomal miRNA，就成了．我的部分將改成TGFB1 induced ECM remodeling，也與TME有關．雅雯/Allen這一塊若是著重于secretory factors 或是要提invsion/migration等也都和TME可以連上關係．陣容堅強的子計劃一就更不用說了，Johnson正好可以把CTLA4/PDL1/IDO1等寫進來． Just want to share some thoughts~ ------------------------ Ya-Wen Chen Sep 23 to me, David, 張書銘, 郭靜娟, 劉滄梧, Shih, 李岳倫, Shine-Gwo, 蕭振仁醫師 Dear all We are doing the exosome in lymph node metastasis. Maybe I am OK to propose that. By the way, Alan is working on GDF10 (secreted protein?) involved in TGFB signaling (GDF10的基因表現會受 TGF-β-TGFBR3的訊息傳導路徑). SF+Alan for TGFB signaling David+ Ya-Wen for miRNA in exosome 夏博會打我....他寫完了... Best, ------------------------ Janelle Kuo Sep 23 to Dr. 劉柯俊, Ya-Wen, me, 蕭振仁醫師, Shine-Gwo, 李岳倫, Shih, 劉滄梧, 張書銘, David 素芳 "Tissue microenvironment of oral cancer" fit 獅子所長先前的建議所以妳的整合型計畫不寫 "folate and methylation了"，是嗎？向大會報告先前因去法國巴黎泡妞而miss我們會議的劉柯大伯也有意願要加入整合型計畫的團隊或者Johnson可以和大伯先討論一下CTLA4/PDL1/IDO1的部份再看看要如何排列組合我也把大伯加入我們的email群組中這兩天還在忙缺口也是先把這塊搞定再說囉娟 ------------------------ Su-Fang Lin <sflin1@gmail.com> Sep 23 to Janelle, 陳雅雯所以妳的整合型計畫不寫 "folate and methylation了"，是嗎？是的，癌細胞形成後，folate過多反倒促進癌細胞生長．整合型這邊我想由OSF/collagen/DDR1這邊下手，是下午在寫另一個chemoprev drug時理出來的想法．希望能成功! Oh Yeah~ 下班前打電話給妳是雅雯過來跟我說妳可能得忙IDO1那邊的東西而沒時間寫chemoprevention子計劃．所以... 現在怎麼樣? I am ready for this part. 妳可以把Nrf2那邊 (and EGCG, if any) 寄給我，另外楊順發主任後來有寄相關的資料給妳嗎? 有的話是不是可以一併寄過來，讓我們衝衝版面．啊，對了，忘記妳有沒有把他的名字放在子計劃四的Co-PI. 記得昨天妳說他是這麼要求的! (he seems to be a nice guy!) ------------------------ Alan Yueh-Luen Lee 李岳倫 Sep 24 to Ya-Wen, me, David, 張書銘, 郭靜娟, 劉滄梧, Shih, Shine-Gwo, 蕭振仁醫師 Tissue Microenvironment is great. I love it. Alan ------------------------ 陳雅雯 <ywc@nhri.org.tw> Sep 24 to Alan Yueh-Luen., me, David, 張書銘, 郭靜娟, 劉滄梧, Shih, Shine-Gwo, 蕭振仁醫師 David It is real that the title is changed. Best, Ya-Wen ------------------------ Janelle Kuo Sep 26 to Dr. 劉滄梧, Dr. 江士昇, Dr. 張書銘, Dr. 陳雅雯, Dr. 李岳倫, me, Dr. 夏興國 Dear all 大家熬了幾天夜今天下午阿碰已成功把缺口計畫交出去後預祝大成功！！！隨後劉柯、素芳、Johnson、和我在壹咖啡討論整合型計畫一事。幾經討論後大家評估時程很趕 (下週二前需繳交) 許多人目前還在國外還有隨之而來的 scientific review rehearsal 真的忙不過來因此決定先下車希望這一年好好討論與準備明年出擊這個決定很對不起Jeffery與David 因為他們兩位的LOI已繳交只能建議兩位看是否有其他團隊的組成機會或以個人型計畫先送在此先向各位報告目前進度希望週末愉快靜娟 ------------------------ 陳雅雯 Sep 26 to 郭靜娟, 劉滄梧, Shih, 張書銘, 李岳倫, me, Shine-Gwo Dear all Thanks for your hard working. Keep discussing and collaborating. We can apply next grant together soon. Have a nice weekend and see you guys soon. (ps. 仙貝己買一些了, Omiyaga is preparing!) Best, Ya-Wen ------------------------ 張書銘 Sep 29 to 郭靜娟, 劉滄梧, Shih, 陳雅雯, 李岳倫, me, Shine-Gwo 下車是一個好的決定希望未來一年可以跟大家好好的討論, 讓我們的研究有更好的integration. 謝謝大家! Jeffrey 刪除編輯回應

Our Thoughts (桀靜精微雷風相薄)

Pages

Oct 3, 2014

2015 MOST PPG

2015 MOST PPG

2015/05/15 新方向

2015/05/08 email 紀錄

2015/05/07 開會紀錄

Small containers, important cargo

Extracellular vesicles as carriers of microRNA, proteins and lip

陽明大學-臺北榮總腫瘤免疫研究團隊重要突破：頭頸癌腫瘤微環境解密

Preconditioning the ECM for fibrosis

The polyphenol EGCG and luteolin inhibits TGFb induced myoblast

ECM stiffness paves the way for tumor cells

Fwd: 萊富蕙敏~~TO:劉柯俊老師

2014/09/18 – 09/29 (上車與下車的回憶)

No comments:

Post a Comment