医科学専攻

  • Master's Courses 
    修士課程
  • Doctoral Courses 
    博士課程

Investigative Pathology病態病理学

  • 難治性疾患
  • ゲノム
  • 分子病理
  • 病理診断
  • 人体病理学
  • 外科病理学
  • 分子病理学
  • 分子生物学

STAFF

Professor

  • Furukawa, ToruProfessor. 古川 徹 教授

Other Faculty / Staff

  • Omori, Yuko
    Assistant Prof. 大森 優子 助教
  • Hirose, Katsuya
    Research Associate, 廣_ 勝也 助手

CONTACT

TEL:+81-22-717-8048
E-MAIL:toru.furukawa*med.tohoku.ac.jp
(「*」を「@」に変換してください)

OUTLINE

We carried out research of intractable diseases with employing advanced molecular pathobiological techniques and genome analysis. Selected topics of our research are as follows:
1. Pancreatic cancer is characterized by persisting activation of ERK/MAPK. We discovered that the ERK/MAPK activation was a result of synergistic effects of mutated KRAS and inactivation of DUSP6, which resulted in transcriptional activation of downstream targeted molecules of ERK including AURKA, SON, and miRNAs that were useful as biomarkers and therapeutic targets. Moreover, we developed a system for testing precision medicine in pancreatobiliary cancers using organoids and genome analysis.
2. Intraductal papillary mucinous neoplasm of the pancreas (IPMN) is characterized by mucinous ductal dilatation lined by papillary neoplastic cells. We demonstrated pathological characteristics of this neoplasm and identified a specific molecular alteration, namely, GNAS mutation. In vitro functional analyses showed that the mutated GNAS induced global changing of gene expressions including upregulation of mucin genes in pancreatic ductal cells. We developed a genetically engineered mouse model capable of conditional expression of the mutated GNAS and demonstrated that the model mouse was able to develop IPMN by synergistic pancreas-specific expression of the mutated GNAS and a mutated Kras. Development of invasive cancer in IPMNs may pursue three distinctive pathways.

当分野では難治性疾患を対象に、最先端のゲノムワイドな分子解析を取り入れた次世代の病理学研究を推進している。
1. 膵臓癌では変異KRASを含む活性化信号にERK/MAPK特異的脱リン酸化酵素であるDUSP6の不活化が相まることでERK/MAPKが恒常的に活性し、活性化ERK/MAPKにより誘導される遺伝子のゲノムワイドスクリーニングで膵癌の悪性形質を担い,かつ、標的化により診断や治療に応用できる分子を同定した。外科切除された癌腫からオルガノイドを樹立し、ゲノム解析によって分子標的を同定し、標的薬剤の効果をオルガノイドで検証することで個別化治療を進められることを示した。
2. 膵管内乳頭粘液性腫瘍(IPMN)は粘液が貯留した膵管拡張を来す特異な膵腫瘍である。我々はIPMNの病理学的特徴を世界に先駆けて明らかにし,また、ゲノム解析によりIPMN特異的な分子異常であるGNAS変異を同定した。変異GNASを膵管上皮由来培養細胞へ導入するとcAMP上昇、PKA活性化,粘液遺伝子発現上昇を伴う大規模な遺伝子発現変化を認めた。変異GNASをコンディショナルに発現できるマウスモデルを作成し、変異Krasと同時に膵特異的に発現させるとIPMN様腫瘍が発生した。IPMNが浸潤がんに進展する過程について3つのパターンがあることを見出した。

  • Pathological review
    病理診断

  • Cell culture experiments
    細胞培養実験

ARTICLE

1. Kobayashi T, et al. Pathways for the development of multiple epithelial types of intraductal papillary mucinous neoplasm of the pancreas. J Gastroenterol 56, 581592, 2021.
URL:https://doi.org/10.1007/s00535-021-01783-2

2. Omori Y, et al. Serine/threonine kinase 11 plays a canonical role in malignant progression of KRAS-mutant and GNAS-wild-type intraductal papillary mucinous neoplasms of the pancreas. Ann Surg
URL:https://doi.org/10.1097/SLA.0000000000004842

3. Ishikawa T, et al. Whole exome sequencing and establishment of an organoid culture of the carcinoma showing thymus-like differentiation (CASTLE) of the parotid gland. Virchows Arch 478: 1149 1159, 2021.
URL:https://doi.org/10.1007/s00428-020-02981-8

4. Takai E, et al. Whole-exome sequencing reveals new potential susceptibility genes for Japanese familial pancreatic cancer. Ann Surg.
URL:https://doi.org/10.1097/SLA.0000000000004213

5. Shiihara M, et al. Development of a system combining comprehensive genotyping and organoid cultures for identifying and testing genotype-oriented personalized medicine for pancreatobiliary cancers. Eur J Cancer 148(5):239-250, 2021
URL:https://doi.org/10.1016/j.ejca.2021.01.047

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