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Blocking proliferation signaling has shown limited benefit in clinical treatment of pancreatic ductal adenocarcinoma, highlighting the urgent need to deeply understand proliferation signaling and develop new therapeutic strategies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>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-\u03b1 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our findings revealed the role of MMP-28 and EGFR in generation of sustaining proliferation signaling and provided a new therapy strategy for PDAC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13046-025-03323-9","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T05:30:41Z","timestamp":1740375041000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Reciprocal regulation of MMP-28 and EGFR is required for sustaining proliferative signaling in PDAC"],"prefix":"10.1186","volume":"44","author":[{"given":"Zhengtao","family":"Hong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linghao","family":"Xia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingbo","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2934-0880","authenticated-orcid":false,"given":"Xueli","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"key":"3323_CR1","doi-asserted-by":"publisher","unstructured":"Siegel, R. 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