Molecular mechanism of subtype shift underlying plasticity and therapy-resistance in glioblastoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07566
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kanazawa University
• Principal Investigator: Kobayashi Masahiko 金沢大学, がん進展制御研究所, 助教 (70285633)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: グリオーマ

Outline of Final Research Achievements

Glioblastoma (GBM), the most aggressive type of brain tumor, is classified into some subtypes in which mesenchymal subtype GBM is therapy-resistant. Radiation and temozolomide are main therapeutics for GBM, however, recurrence occurs due to therapy-resistance through proneural-mesenchymal transition. The mechanisms of this subtype-shift and therapy-resistance in mesenchymal subtype have been unclear. To address these questions, we focused on a mesenchymal subtype and therapy-resistance marker, CD44. In this study, we found that hypoxia and OLIG2 suppressed CD44 levels and therapy-resistance. RNA-seq analysis showed lysosome-related genes were up-regulated in the CD44-high subpopulation. A lysosome inhibitor increased the sensitivity of CD44-high subpopulation to temozolomide and radiation.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

膠芽腫（グリオブラストーマ）の細胞系譜転換のメカニズムを明らかにし、治療抵抗性に働く経路を特定した本研究成果をさらに発展させることによって、治療抵抗性腫瘍に対しても、これまでの治療法をより効果的に作用させる方法の開発につながるものと考えられる。