Conclusions
Our findings revealed the role of MMP-28 and EGFR in generation of sustaining proliferation signaling and provided a new therapy strategy for PDAC.
Methods
By leveraging clinical data and data from the TCGA and GDSC datasets, we investigated the association between MMP-28 expression and the sensitivity to EGFR inhibitors as well as the prognosis of PDAC. Transcriptomic and biological experiments explore the regulatory role of MMP-28 on the EGFR signaling pathway. Additionally, in vitro and in vivo studies are employed to evaluate MMP-28 as a biomarker for sensitivity to EGFR inhibitors.
Results
We found that MMP-28, a metalloproteinase, was significantly associated with the sensitivity to EGFR inhibitors. Furthermore, MMP-28 could promote PDAC growth and metastasis. Mechanistically, MMP-28 facilitated the maturation and release of the TGF-α precursor, thus promoting EGFR activation. In return, EGFR upregulated MMP-28 through AP-1-mediated transcription, forming a positive feedback loop that provided sustaining proliferation signaling for PDAC. Subsequently, MMP-28 was identified to predict the response to EGFR inhibitors and recognize responsive patients. Conclusions: Our findings revealed the role of MMP-28 and EGFR in generation of sustaining proliferation signaling and provided a new therapy strategy for PDAC.