Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion

Abstract

Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF-RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C-IQGAP1-MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.

Data availability

-Sequencing data have been deposited in DDBJ under accession codes DRA011537.-All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1-7, Figure 2-figure supplement 1, Figure 2-figure supplement 2, Figure 2-figure supplement 3, Figure 3-figure supplement 1, Figure 3-figure supplement 2, Figure 4-figure supplement 1, Figure 6-figure supplement 1, Figure 7-figure supplement 1, Supplementary File 1 Table 1, and Supplementary File 1 Table 2.

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Article and author information

Author details

  1. Akikazu Harada

    Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Shinji Matsumoto

    Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Yoshiaki Yasumizu

    Laboratory of Experimental Immunology, WPI Frontier Immunology Research Center, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9872-4909
  4. Toshiyuki Akama

    Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Hidetoshi Eguchi

    Gastrointestinal Surgery, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Akira Kikuchi

    Department of Molecular Biology and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Japan
    For correspondence
    akikuchi@molbiobc.med.osaka-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3378-9522

Funding

Ministry of Education, Culture, Sports, Science and Technology (16H06374)

  • Akira Kikuchi

Ministry of Education, Culture, Sports, Science and Technology (18H04861)

  • Akira Kikuchi

Ministry of Education, Culture, Sports, Science and Technology (18H05101)

  • Akira Kikuchi

Yasuda Memorial Medical Foundation

  • Akira Kikuchi

Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care

  • Akira Kikuchi

Osaka University

  • Akira Kikuchi

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lynne-Marie Postovit, University of Alberta, Canada

Ethics

Animal experimentation: All protocols used for the animal experiments in this study were approved by the Animal Research Committee of Osaka University, Japan (No. 26-032-048). This information is mentioned in the 'Materials and Methods' section.

Version history

  1. Received: January 20, 2021
  2. Preprint posted: February 24, 2021 (view preprint)
  3. Accepted: September 29, 2021
  4. Accepted Manuscript published: September 30, 2021 (version 1)
  5. Version of Record published: November 17, 2021 (version 2)

Copyright

© 2021, Harada et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Akikazu Harada
  2. Shinji Matsumoto
  3. Yoshiaki Yasumizu
  4. Toshiyuki Akama
  5. Hidetoshi Eguchi
  6. Akira Kikuchi
(2021)
Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion
eLife 10:e66721.
https://doi.org/10.7554/eLife.66721

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https://doi.org/10.7554/eLife.66721

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