Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer

Takeshi Koujima, Hiroshi Tazawa, Takeshi Ieda, Hiroyuki Araki, Takuro Fushimi, Ryohei Shoji, Shinji Kuroda, Satoru Kikuchi, Ryuichi Yoshida, Yuzo Umeda, Fuminori Teraishi, Yasuo Urata, Hiroyuki Mizuguchi, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells.

Original languageEnglish
Pages (from-to)107-117
Number of pages11
JournalMolecular Therapy - Oncolytics
Volume17
DOIs
Publication statusPublished - Jun 26 2020

Keywords

  • ERK
  • adenovirus
  • invasion
  • migration
  • nerve
  • p53
  • pancreatic cancer
  • telomerase
  • tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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