Establishment of analysis method for spatiotemporal control of interstitial remodeling

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22563
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Osaka University
• Principal Investigator: Kikuchi Akira 大阪大学, 医学系研究科, 教授 (10204827)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: Wnt5a / 炎症 / 大腸腫瘍 / 1細胞シーケンス / 線維芽細胞

Outline of Final Research Achievements

While mesenchymal tissues are essential for the maintenance of homeostasis of tissue-specific stem cells, it also promotes the aggressiveness of tumorigenesis and inflammation. In addition, spatial localization of fibroblasts is important for the maintenance of stemness. We found that Wnt5a is expressed in fibroblasts beneath of the ulcerative legions in the colon, and the fibroblasts do not express typical markers of activated fibroblasts. In this study, using AOM/DSS-induced inflammatory colon cancer mouse model, we identified new type of fibroblasts which express Wnt5a by the combination of single cell RNA sequence and imaging technology. The fibroblasts were localized to the lesion surrounding tumors and knockout of Wnt5a decreased numbers of the different set of fibroblasts, as well as the reduction of numbers and sizes of tumors. The results suggest that spatial and temporal regulation of remodeling of inflammatory cells is important for the tumorigenesis based on inflammation.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

近年、１細胞RNAシーケンス法によって様々な臓器を構成する細胞のサブセットが次々と報告されており、今後これらをリファレンスとして各種疾患発症メカニズムを理解する情報科学的研究が加速すると考えられる。本研究では、炎症誘導性大腸がんをモデルとして、1細胞シーケンス解析とイメージング技術を有機的に結びつけて、Wnt5a発現線維芽細胞を同定し、Wnt5aの発現低下により他の線維芽細胞群の増殖が抑制され、大腸腫瘍形成が阻害されることを明らかにした。この成果により、病態を引き起こす間質リモデリングの時空間的制御の解析法の一端が確立したことから、学術的意義が大きい。