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Published on: September 27, 2024
IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration
Dawn V Jaquish1, Peter T Yu, David J Shields
1Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, 3855 Health Sciences Drive, San Diego, CA 92093-0987, USA.
Abstract:
The RON receptor tyrosine kinase (RTK) is overexpressed in the majority of pancreatic cancers, yet its role in pancreatic cancer cell biology remains to be clarified. Recent work in childhood sarcoma identified RON as a mediator of resistance to insulin-like growth factor receptor (IGF1-R)-directed therapy. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants. Using multidimensional protein identification analysis, IGF-1R was identified and confirmed to interact with RON in pancreatic cancer cell lines. IGF-1 induces rapid phosphorylation of RON, but RON signaling did not activate IGF-1R indicating unidirectional signaling between these RTKs. We next demonstrate that IGF-1 induces pancreatic cancer cell migration that is RON dependent, as inhibition of RON signaling by either shRNA-mediated RON knockdown or by a RON kinase inhibitor abrogated IGF-1 induced wound closure in a scratch assay. In pancreatic cancer cells, unlike childhood sarcoma, STAT-3, rather than RPS6, is activated in response to IGF-1, in a RON-dependent manner. The current study defines a novel interaction between RON and IGF-1R and taken together, these two studies demonstrate that RON is an important mediator of IGF1-R signaling and that this finding is consistent in both human epithelial and mesenchymal cancers. These findings demand additional investigation to determine if IGF-1R independent RON activation is associated with resistance to IGF-1R-directed therapies in vivo and to identify suitable biomarkers of activated RON signaling.
Insights
Pancreatic cancer cells utilize the RON receptor tyrosine kinase (RTK) to mediate migration in response to insulin-like growth factor 1 (IGF-1). This study reveals a novel interaction between RON and IGF-1R, highlighting RON
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The receptor tyrosine kinase (RTK) RON is overexpressed in most pancreatic cancers, but its function is unclear.
- Previous research linked RON to resistance against insulin-like growth factor receptor (IGF1-R) therapies in childhood sarcoma.
Purpose of the Study:
- To investigate the role of RON in pancreatic cancer cell biology.
- To identify novel proteins interacting with RON in pancreatic cancer cells.
Main Methods:
- Multidimensional protein identification analysis to find RON interactants.
- Confirmation of IGF-1R interaction with RON in pancreatic cancer cell lines.
- Scratch assays to assess cell migration and RON-dependent signaling.
Main Results:
- Insulin-like growth factor 1 (IGF-1) was identified as an interacting partner of RON.
- IGF-1 rapidly phosphorylates RON, but signaling is unidirectional (RON does not activate IGF-1R).
- IGF-1-induced pancreatic cancer cell migration is dependent on RON signaling, involving STAT-3 activation.
Conclusions:
- A novel interaction between RON and IGF-1R is defined in pancreatic cancer.
- RON acts as a key mediator of IGF-1R signaling, consistent across epithelial and mesenchymal cancers.
- Further research is needed to explore RON's role in therapeutic resistance and identify biomarkers.
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