Elucidation of the difference in extracellular matrix remodeling ability of pancreatic stellate cells depending on pancreatic cancer phenotype via organoid models

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H06258
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Kyushu University
• Principal Investigator: IKENAGA Naoki 九州大学, 大学病院, 助教 (90759755)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 膵癌 / オルガノイド / 膵星細胞 / 癌周囲微小環境 / 基質リモデリング

Outline of Final Research Achievements

This study was performed to classify the phenotype of pancreatic cancer organoids derived from human pancreatic tissue and to clarify the difference in the extracellular matrix (ECM) remodeling ability of activated pancreatic stellate cells (PSCs) depending on the phenotypes. The organoids maintained the morphology of the pancreatic tissues, and phenotype classification was possible based on the niche factors dependency and the tumor differentiation. We established a three-dimensional co-culture model using the organoids and PSCs, and observed how the pancreatic cancer cells invade the ECM. These revealed that the basement membrane destruction by PSCs via MMP2 and MT1-MMP. In the future, we challenge to elucidate the differences in ECM remodeling by PSCs depending on each pancreatic cancer phenotype and to develop a personalized treatment that controls cancer cell invasion.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

膵癌の予後を規定する癌浸潤メカニズムを解明する上で、従来の細胞株のような単一的なphenotypeではなく、患者個々の膵癌組織から樹立した膵癌オルガノイドを用いることで様々な膵癌phenotypeに応じた浸潤形態を観察可能となった。本研究では、この膵癌オルガノイドと膵星細胞の三次元共培養モデルを作製することで、より生体内を反映した環境での浸潤形態を観察可能となり、膵星細胞のMMP2及びMT1-MMPを介した膵癌基底膜破壊が膵癌細胞浸潤に関わっていることを解明した。今後は、樹立した様々な膵癌phenotypeに応じた浸潤過程の差違を明らかにすることで、膵癌患者の予後改善に寄与し得ると考えられる。