{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:04:41Z","timestamp":1780463081506,"version":"3.54.1"},"reference-count":43,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,24]],"date-time":"2026-05-24T00:00:00Z","timestamp":1779580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic tumors frequently exhibit calcification, suggesting potential osteogenic-related phenotypic plasticity. This study aimed to systematically evaluate whether pancreatic ductal adenocarcinoma (PDAC) cells acquire osteogenic-like features under induction conditions and to assess the associated phenotypic and molecular changes. PDAC cell lines and non-malignant pancreatic epithelial cells were subjected to osteogenic induction. Mineralization, alkaline phosphatase (ALP) activity, osteogenic marker expression, and malignant phenotypes were evaluated. RNA sequencing was performed at defined time points to characterize transcriptional changes. Pharmacological inhibition of MEK and siRNA-mediated knockdown of RUNX2 were applied to examine the involvement of MAPK\u2013ERK signaling and downstream transcriptional regulation. Osteogenic induction led to calcium deposition and increased ALP activity in a subset of PDAC cell lines, accompanied by upregulation of osteogenic-associated markers, including RUNX2 and SPP1. Induced cells exhibited reduced migration, clonogenicity, invasion, and proliferation. Transcriptomic analysis revealed activation of osteogenesis-related and calcium-transport pathways, along with downregulation of cell cycle programs. MAPK\u2013ERK signaling was activated during induction, and MEK inhibition attenuated RUNX2 and ALP expression as well as mineralization-associated changes. Furthermore, RUNX2 knockdown reduced ALP expression and mineralization levels, indicating its contribution to the osteogenic-like phenotype. PDAC cells can acquire osteogenic-like features under defined induction conditions, accompanied by coordinated transcriptional reprogramming and reduced malignant phenotypes. The observed mineralization-associated phenotypes may reflect a combination of active processes and passive calcium deposition. In addition, the MAPK\u2013ERK\u2013RUNX2 axis appears to be involved in this process, although it may reflect a broader adaptive or stress-associated reprogramming rather than lineage commitment. These findings provide insight into the potential relationship between tumor calcification and phenotypic plasticity in PDAC.<\/jats:p>","DOI":"10.3390\/ijms27114725","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:45:08Z","timestamp":1779673508000},"page":"4725","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Osteogenic-like Phenotypic Reprogramming Is Associated with Reduced Malignant Behaviors in Pancreatic Cancer Cells Involving MAPK\u2013ERK Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8151-2179","authenticated-orcid":false,"given":"Gong","family":"Chen","sequence":"first","affiliation":[{"name":"Department of General, Visceral & Transplant Surgery, Section Surgical Research, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General, Visceral & Transplant Surgery, Section Surgical Research, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General, Visceral & Transplant Surgery, Section Surgical Research, University of Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Wei","sequence":"additional","affiliation":[{"name":"First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), Heidelberg University, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1016\/j.cell.2023.02.014","article-title":"Pancreatic cancer: Advances and challenges","volume":"186","author":"Halbrook","year":"2023","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1007\/s00261-017-1182-8","article-title":"Calcified pancreatic and peripancreatic neoplasms: Spectrum of pathologies","volume":"42","author":"Verde","year":"2017","journal-title":"Abdom. 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