The accumulation of extracellular matrix induces immunosuppressive microenvironment and treatment resistance in pancreatic cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17672
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Tohoku University
• Principal Investigator: Aoki Shuichi 東北大学, 大学病院, 助教 (30844451)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: tumor microenvironment / pancreatic cancer / immunotherapy / extracellular matrix / hypoxia

Outline of Final Research Achievements

We performed nCounter Analysis, a novel integrated RNA sequence technique, using resected pancreatic cancer samples after preoperative chemotherapy (NAT) at our department. The expression of MET, LAMB2, and COL17A1 was significantly increased in the treatment-resistant group, and patients with high MET-expression significantly occurred postoperative liver metastasis and showed poor prognosis. We established MET-knockout pancreatic cancer cell lines by CRISPR/cas9 method. In 3-D culture, MET-knockout inactivated YAP-CTGF pathway and decreased expression of extracellular matrix such as Collagen I. In an orthotopic mouse model, MET inhibition suppressed liver metastases and reduced accumulation of extracellular matrix within tumor. Finally, MET inhibition increased the infiltrated CD8 T cells within the tumor by improving the hypoxic environment to normoxia.

Free Research Field

Surgical oncology

Academic Significance and Societal Importance of the Research Achievements

既存の術前化学療法を行なっても、MET高発現膵癌はMET-YAP-CTGF経路による細胞外マトリックス産生や細胞接着の亢進により、肝転移を誘導し治療耐性をもたらす。MET阻害による細胞外マトリックス産生の低下は、低酸素環境の改善による癌微小環境の再構築をもたらし、抗腫瘍免疫の活性化につながる。MET阻害剤と免疫チェックポイント阻害剤との併用は、既存の化学療法より優れた治療効果をもたらす可能性があり、膵癌術前治療の新たな治療戦略となり得る。