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Home > Organization > Divisions and Independent Research Units > Group for Translational Research > Division of Molecular and Cellular Medicine > Research Projects > Understanding oncogenic mechanism caused by microRNA and exosome, and the practical application for diagnosis and treatment

Understanding oncogenic mechanism caused by microRNA and exosome, and the practical application for diagnosis and treatment

Understanding oncogenic mechanism caused by microRNA and exosome, and the practical application for diagnosis and treatment

Recently, accumulating evidence of extracellular vesicles, so-called exosomes, have revealed its involvement in pathogenesis of many diseases and now enormous attention is focused on the biological significance of exosomes. Exosomes secreted from various types of cells contain functional molecules such as proteins, microRNAs (miRNAs), and mRNAs, which are transferred to not only proximal cells, but also distant cells. Cancer cells package favorable molecules for their survival into exosomes and deliver them to surrounding cells. Interestingly, cancer cells also utilize exosomes secreted by surrounding cells. In our laboratory, we aim to deepen the understanding of exosome biology and to develop new treatment and diagnostic methods by revealing molecular mechanisms on exosome-mediated tumorigenesis and malignancy. Moreover, as biologically important miRNAs are responsible for many diseases; our laboratory is also working on the elucidation of carcinogenesis and malignant mechanism driven by miRNAs.

Project 1: Elucidating exosome-mediated oncogenic transformation

Our research focus is to elucidate the molecular mechanisms underlying cancer malignancy mediated by exosomes that are associated with proliferation, invasion and metastasis, and to investigate the cellular mechanisms of cancer microenvironment and pre-metastatic niche formation. For example, miRNA-containing exosomes secreted by cancer cells cause intratumoral angiogenesis, and in turn, exosomes and exosomal miRNAs are involved in the process of metastasis. Furthermore, we have reported that metastatic cancer cell-derived exosomes destroy the blood-brain barrier and contribute to brain metastasis. Besides cancer cell-derived exosomes, we have reported that exosomes secreted from non-cancerous cells such as bone marrow-derived mesenchymal stem cells, controlled dormancy status of breast cancer cells, leading to long-term relapse. Ongoing research in our laboratory are, the study of peritoneal metastasis in ovarian cancer caused by exosomes and the elucidation of the exosomes function in cancer microenvironment in diffuse type gastric cancer.

Project 2: Development of novel cancer therapy targeting exosomes

We aim to apply the data obtained from functional analysis of cancer exosomes, for the development of new cancer treatments. Our attempt is to attenuate cancer cells by inhibiting malignant exosomes that contribute to the formation of the cancer microenvironment and pre-metastatic niche. Furthermore, we are developing a tool which can selectively remove cancer-derived exosomes from the patient’s blood.

Project 3: Development of exosome-based liquid biopsy

Exosomes are secreted from various cell types and are present in body fluids such as blood and urine. We consider that capturing circulating exosomes for diagnostic purposes would be a beneficial method because it is possible to collect blood and urine samples with minimum invasiveness. Since exosomes contain proteins and miRNAs, some of which are cell type-specific, it is very important to consider what kind of molecules we use as “cancer markers” and how to detect them efficiently. Our laboratory has developed a highly sensitive and high-throughput exosome detection system. Using this method, we successfully detected exosomes contained in the sera of colorectal cancer patients. Currently, diagnostic methods targeting exosomes in the blood from pancreatic ductal carcinoma patients and in the urine from bladder cancer patients are under development. Likewise, we have been searching novel miRNA biomarkers in the blood for the realization of early detection of cancer.

Project 4: Elucidating molecular mechanisms of miRNAs in tumorigenesis and the therapeutic application

Abnormal expression of miRNA, which is a fine tuner of gene expression, is observed in many diseases including cancer. We have been developing new therapeutic strategies by understanding the molecular function of miRNAs, restoring appropriate expression levels of miRNAs, and modulating miRNA downstream target gene expression. Recently, we have reported miRNAs that are involved in drug resistance of lung cancer and osteosarcoma and miRNAs that suppress the invasion of liver cancer. In addition to this, based on histopathological evidence, the expression and functional analysis of miRNA were conducted using malignant bone and soft tissue tumors. We have identified several miRNAs involved in malignant phenotype, which are currently under investigation towards clinical application.

関連論文報告(原著論文)

2015

  1. Fujita Y, Araya J, Ito S, Kobayashi K, Kosaka N, Yoshioka Y, Kadota T, Hara H, Kuwano K, Ochiya Takahir. Suppression of autophagy by extracellular vesicles promotes myofibroblast differentiation in COPD pathogenesis. J Extracell Vesicles, 4:28388, 2015
  2. Fujita Y, Yagishita S, Hagiwara K, Yoshioka Y, Kosaka N, Takeshita F, Fujiwara T, Tsuta K, Nokihara H, Tamura T, Asamura H, Kawaishi M, Kuwano K, Ochiya T. The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther, 23:717-727, 2015
  3. Hagiwara K, Gailhouste L, Yasukawa K, Kosaka N, Ochiya T. A robust screening method for dietary agents that activate tumour-suppressor microRNAs. Sci Rep, 5:14697, 2015
  4. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, Lötvall J, Nakagama H, Ochiya T. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat Commun, 6:6716, 2015

2014

  1. Fujiwara T, Katsuda T, Hagiwara K, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Kubota D, Kondo T, Ichikawa H, Yoshida A, Kobayashi E, Kawai Akira, Ozaki T, Ochiya T. Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells. Stem Cells, 32:959–973, 2014
  2. Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal, 7:ra63, 2014
  3. Yoshioka Y, Kosaka N, Konishi Y, Ohta H, Okamoto H, Sonoda H, Nonaka R, Yamamoto H, Ishii H, Mori M, Furuta K, Nakajima T, Hayashi H, Sugisaki H, Higashimoto H, Kato T, Takeshita F, Ochiya T. Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat Commun, 5:3591, 2014

2013

  1. Gailhouste L, Gomez-Santos L, Hagiwara K, Hatada I, Kitagawa N, Kawaharada K, Thirion M, Kosaka N, Takahashi RU, Shibata T, Miyajima A, Ochiya T. miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells. Hepatology, 58:1153-1165, 2013
  2. Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K, Oki K, Takeshita F, Sakai Y, Kuroda M, Ochiya T. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep, 3:1197, 2013
  3. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase 2(nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem, 288:10849-10859, 2013
  4. Uchino K, Takeshita F, Takahashi RU, Kosaka N, Fujiwara K, Naruoka H, Sonoke S, Yano J, Sasaki H, Nozawa S, Yoshiike M, Kitajima K, Chikaraishi T, Ochiya T. Therapeutic Effects of MicroRNA-582-5p and -3p on the Inhibition of Bladder Cancer Progression. Mol Ther, 21:610-619, 2013
  5. Yoshioka Y, Konishi Y, Kosaka N, Katsuda T, Kato T, Ochiya T. Comparative marker analysis of extracellular vesicles in different human cancer types. J Extracell Vesicles, 2:20424, 2013

2012

  1. Hagiwara K, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Ochiya T. Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity. Sci Rep, 2:314, 2012
  2. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T. Competitive interactions of cancer cells and normal cells via secretory microRNAs. J Biol Chem, 287:1397-1405, 2012
  3. Yoshioka Y, Kosaka N, Ochiya T, Kato T. Micromanaging iron homeostasis - Hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem, 287:34110-34119, 2012

2011

  1. Osaki M, Takeshita F, Sugimoto Y, Kosaka N, Yamamoto Y, Yoshioka Y, Kobayashi E, Yamada T, Kawai A, Inoue T, Ito H, Oshimura M, Ochiya T. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Mol Ther, 19:1123-1130, 2011
  2. Yamamoto Y, Yoshioka Y, Minoura K, Takahashi RU, Takeshita F, Taya T, Horii R, Fukuoka Y, Kato T, Kosaka N, Ochiya T. An integrative genomic analysis revealed the relevance of microRNA and gene expression for drug-resistance in human breast cancer cells. Mol Cancer, 10:135, 2011

2010

  1. Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem, 285:17442-17452, 2010
  2. Kosaka N, Izumi H, Sekine K, Ochiya T. microRNA as a new immune-regulatory agent in breast milk. Silence, 1:7, 2010
  3. Takeshita F, Patrawala L, Osaki M, Takahashi R, Yamamoto Y, Kosaka N, Kawamata M, Kelnar K, Bader AG, Brown D, Ochiya T. Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes. Mol Ther, 18:181-187, 2010