The invasion mechanism of MELF pattern in endometrioid carcinoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16171
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Osaka University
• Principal Investigator: Tahara Shinichiro 大阪大学, 大学院医学系研究科, 助教 (20792584)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: MELF / NNMT / PD-L1 / Laser microdissection / RNA sequencing

Outline of Final Research Achievements

We searched for genes preferentially expressed in the invasive front area of endometrioid carcinoma (EC) with the MELF pattern using laser microdissection and RNA sequencing, and showed that nicotinamide N-methyltransferase (NNMT) is related to MELF pattern invasiveness. Immunohistochemical analyses confirmed high NNMT expression in the invasive front area of the MELF pattern, and using EC cell lines, NNMT promoted migration, invasion, colony formation, epithelial-mesenchymal transition (EMT) and chemoresistance. Moreover, we performed immunohistochemical analysis of the distribution of PD-L1 (programmed cell death-ligand 1) expressing cells in G1 with MELF pattern. In cases of G1 with MELF pattern, tumor cells expressed PD-L1 significantly higher in invasive front area than in surface area. Significant therapeutic effect can be expected by applying PD-1/PD-L1 immunotherapy to the treatment of G1 with MELF.

Free Research Field

子宮体癌

Academic Significance and Societal Importance of the Research Achievements

子宮体部の類内膜癌には形態学的に悪性度が低く予後が良いとされるGrade 1であるにもかかわらず、高い浸潤性を示すMELF (microcystic, elongated, and fragmented) patternという特徴的な形態を有するものがある。MELF patternは組織形態から提唱された概念であるが、その分子メカニズムに関してははっきりしていなかった。本研究ではNNMTがMELFの浸潤メカニズムに関わっていることを示した。またMELF patternを有する類内膜癌にPD-L1阻害薬が有用な治療となる可能性を示した。