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Recent studies have indicated that tumors exhibit increased malignancy following the acquisition of chemoresistance. However, the underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanisms by which PDAC cells acquire GEM resistance and how this resistance drives cancer progression, focusing on identifying the key molecular drivers involved in these processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We established GEM-resistant PDAC cell lines (GEM-Panc-1 and GEM-MIA PaCa-2) and characterized their malignant phenotypes using migration, invasion, proliferation, and sphere-formation assays, as well as\n                      <jats:italic>in vivo<\/jats:italic>\n                      models for tumor growth, tumor initiation, and metastasis. The functional role of \u03b24 integrin (encoded by\n                      <jats:italic>ITGB4<\/jats:italic>\n                      ) was evaluated using stable knockdown and overexpression systems. To investigate the regulatory mechanisms, we employed RNA sequencing, chromatin immunoprecipitation (ChIP), and promoter reporter assays. Clinical relevance was assessed using TCGA datasets and Kaplan\u2012Meier analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GEM-resistant PDAC cells exhibited enhanced invasive potential, tumorigenicity, and stemness, which coincided with the upregulation of \u03b24 integrin. Knockdown of \u03b24 integrin in GEM-resistant cells attenuated these malignant properties and partially restored GEM sensitivity, whereas its ectopic expression in parental cells conferred aggressive phenotypes. Clinically, high expression of\n                      <jats:italic>ITGB4<\/jats:italic>\n                      and its ligand, the laminin-332 subunit genes (\n                      <jats:italic>LAMA3<\/jats:italic>\n                      ,\n                      <jats:italic>LAMB3<\/jats:italic>\n                      , and\n                      <jats:italic>LAMC2<\/jats:italic>\n                      ), correlated with poor overall survival in PDAC patients. Mechanistically, the \u03b24 integrin\/laminin-332 axis promoted cell motility and GEM resistance via Src activation. Furthermore, acquired GEM resistance epigenetically supports the activation of\n                      <jats:italic>ITGB4<\/jats:italic>\n                      transcription, which is associated with \u03b2-catenin nuclear translocation and p300-mediated histone H3 acetylation (H3K27ac) at the\n                      <jats:italic>ITGB4<\/jats:italic>\n                      promoter.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that GEM-induced \u03b24 integrin expression, potentially supported by \u03b2-catenin\/p300-mediated epigenetic remodeling, is a critical determinant of GEM resistance and PDAC progression. Targeting the \u03b24 integrin\/laminin-332\/Src signaling axis may provide a promising therapeutic strategy to overcome chemoresistance and improve clinical outcomes in patients with advanced PDAC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03718-2","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T04:46:30Z","timestamp":1777005990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Gemcitabine-induced \u03b24 integrin drives cancer progression and gemcitabine resistance in pancreatic cancer"],"prefix":"10.1186","volume":"45","author":[{"given":"Yoshinobu","family":"Kariya","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruto","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Kariya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiru","family":"Nishita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"3718_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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