Exploring Novel Therapies for IPF-Associated Lung Cancer by Targeting the Mechanisms Sustaining the Activation of Cancer-Associated Fibroblasts

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17174
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: University of Tsukuba
• Principal Investigator: Suzuki Toshio 筑波大学, 医学医療系 臨床腫瘍学/腫瘍内科, 専任講師 (70771856)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 肺癌 / 癌ニッチ / がん関連線維芽細胞 / 細胞間相互作用 / 空間的トランスクリプトーム解析 / 肺癌オルガノイド / EGFR変異陽性肺腺癌 / 薬剤耐性

Outline of Final Research Achievements

There is an urgent need for new therapies targeting the cancer microenvironment, particularly the interactions between cancer cells and fibroblasts. Our research focused on how F2-Isoprostanes (F2-IsoPs) signal between cancer cells and fibroblasts, potentially driving malignancy and treatment resistance through sustained activation of cancer-associated fibroblasts. F2-IsoPs were found to activate fibroblasts in both non-cancerous and cancerous tissues via the Thromboxane-Prostanoid receptor (TPr), an effect reversible by TPr antagonists. Combining TPr antagonists with EGFR-TKI in EGFR-mutant lung cancer reduced drug-resistant cells. However, spatial omics analyses of lung cancer tissues showed no TPr-positive fibroblasts near cancer cells, suggesting other factors may influence pathogenesis, possibly due to limited sample size or additional regulatory mechanisms involving TBXA2R protein.

Free Research Field

呼吸器内科学

Academic Significance and Societal Importance of the Research Achievements

慢性炎症および線維化病態は発癌母地として様々な臓器で問題になり、そこで発生した癌は難治性であることが知られているが、線維化のエフェクター細胞である線維芽細胞と癌細胞の相互作用をターゲットにした治療戦略は確立していない。本研究によってがん関連線維芽細胞がF2-isoprostanesシグナルを介して持続活性化し、癌の難治化を誘導している結果が示唆された。一方、空間オミックス解析ではF2-Isoprostanesの受容体であるThromboxane-Prostanoid receptorの発現は癌細胞に隣接する位置でのみ発現するわけではなく、他のシグナル経路も本病態に関与していることが示唆された。