Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion
- Osaka University, Japan
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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Pancreatic Ductal Adenocarcinoma projectPancreatic Ductal Adenocarcinoma.
Article and author information
Author details
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.
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.
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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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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