The goals of my lab are to study the regulation of cancer and tissue stem cell and to apply the finding in developing cancer therapy and regenerative medicine. We identify a previously unknown mechanism by which PGE2/prostaglandin E receptor 4 (EP4) signaling regulates multiple signaling pathways required for stem cell (SC) homeostasis. We, for the first time, prove that blocking PGE2/EP4 signaling promotes stem cells to release extracellular vesicles (EVs)/exosomes which carry stem cell properties. Non-stem cells can acquire stem cell properties following ingestion of the induced stem cell EVs/exosomes, and can then form tissue in vivo (Stem Cells 2017;35(2):425-444; J Vis Exp 2017; 124, e55736). The EP4 antagonism-induced SC EV-mediated stemness transfer provides a new direction for cancer stem cell-targeting therapy and regeneration medicine.
We further apply the finding on cancer therapy. Due to gastrointestinal toxicity of non-steroidal anti-inflammatory drug and cardiotoxicity of COX-2 inhibitor, use of these agents in cancer prevention remains controversial. We find that PGE2/EP4 signaling elicits expansion of cancer stem cell (CSC) pools in breast tumors (Cancer Discovery 2012;2(9):840-55). Furthermore, we demonstrate that EP4 antagonism, a more selective inhibition of PGE2 signaling, reduces the number of CSCs in tumors and increases chemosensitivity of tumors. EP4 antagonism converts CSCs to chemotherapy-sensitive non-CSCs by triggering EV release, and enhances tumor responses to conventional chemotherapy (Int J Cancer 2018;15;143(6):1440-1455; Cover Story). This finding holds implications for the treatment of chemoresistant carcinomas in the oncology clinic.
To develop regeneration medicine for brain damage, we find that blocking PGE2/EP4 signaling in mesenchymal stem cells (MSCs) increased EV/exosome release and promoted the sorting of specific proteins into the EVs/exosomes. Systemic administration of EP4 antagonist-elicited MSC EVs repairs deficiencies of cognition, learning and memory, inhibits reactive astrogliosis, attenuates extensive inflammation, reduces microglial infiltration into the damaged hippocampus, and increases blood brain barrier integrity of the mice with brain damages (Stem Cells Transl Med 2019;8(7):707-723 FEATURED ARTICLE; Stem Cells Transl Med 2020;9:499–517 R.O.C Taiwan patent 2017 no.I601741; US patent 2021 no.11149277B2). Based on this finding, we develop SC-derived EVs/exosomes as regeneration medicine for brain damage/diseases.
Based on our finding in past years, my lab currently works on the three directions in the fields of cancer biology, cancer therapy and regeneration medicine.
Direction 1: The mechanism of miRNA release from tissue stem cells/cancer cells and its application in regeneration medicine and cancer therapy. (Under the support of 科技部吳大猷先生紀念獎研究計畫).
Direction 2: Investigating roles of proteoglycans in lung tropism of breast cancer metastasis, from the angles of pulmonary vessels and immune cells in the lung pre-metastatic niche. (Under the support of 科技部優秀年輕學者研究計畫)
Direction 3: Developing NHRI-patented induced exosomes (iExo) technology for clinical use (Under the support of 國家衛生研究院競爭育成計畫; In collaboration with 專利專屬授權廠商)
EDUCATION / 學歷
| 2003 – 2007 | Ph.D., Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), CA, USA |
| 2001 – 2003 | M.S., Biochemistry, National Yang-Ming University, Taipei, Taiwan |
| 1997 – 2001 | B.S., Zoology, National Taiwan University, Taipei, Taiwan |
EXPERIENCE / 經歷
| 2019/07 – present | Associate Investigator, Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan |
| 2012/11 – 2019/07 | Assistant Investigator, Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan |
| 2009 – 2012 | Postdoctoral fellow, Whitehead Institute for Biomedical Research/MIT, Boston, MA, USA |
| 2007 – 2009 | Postdoctoral fellow, University of California, Los Angeles (UCLA), CA, USA |
LAB MEMBER / 研究團隊
| 姓名 | 職稱 | 分機 | |
|---|---|---|---|
| 蔡家玄 | 博士後研究員 | 37523 | jstsai@nhri.edu.tw |
| 陳怡如 | 博士後研究員 | 37523 | 100702@nhri.edu.tw |
| 陳詩尹 | 研究助理 | 37523 | ian741@nhri.edu.tw |
| 羅文亭 | 研究助理 | 37523 | winty@nhri.edu.tw |
| 盧俐羽 | 研究助理 | 37523 | n27293031@nhri.edu.tw |
| 許靖亞 | 研究助理 | 37523 | jingya@nhri.edu.tw |
HONOR & AWARDS/ 榮譽獎項
| 2022 | 外泌體專利獲專屬技轉 |
| 2022 | 國家衛生研究院競爭育成計畫得主 |
| 2021 | 中國醫藥大學現代生物醫學講座 |
| 2021 | 中研院生命科學圖書館講座 |
| 2021 | 國家衛生研究院年輕學者研究獎 |
| 2020-2023 | 科技部吳大猷先生紀念獎研究計畫 |
| 2019 | Ta-You Wu Memorial Award (吳大猷獎) |
| 2019-2022 | 科技部優秀年輕學者研究計畫 |
| 2009-2012 | Postdoctoral Fellowship from Susan G. Komen for the Cure |
| 2002 | Young Investigator Awards of International Congress on Hormonal Steroids and Hormones and Cancer, Fukuoka, Japan |
| 2002 | The scholarship of the Medical Scholarship Foundation in Memory of Professor Albert Ly-young Shen, Taiwan |
PUBLICATIONS / 論文著作
NHRI Institutional Repository國家衛生研究院機構典藏
