{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T03:08:24Z","timestamp":1789528104262,"version":"build-2803163510"},"reference-count":51,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"37","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,9,12]]},"abstract":"<jats:p>Current treatments for pancreatic ductal adenocarcinoma (PDAC) fall short of meeting clinical needs, highlighting the urgent need for a comprehensive understanding of PDAC progression, which involves not only biochemical signals but also essential biomechanical cues. Here, we used a CRISPR-Cas9 screen in an orthotopic xenograft model to explore PDAC dynamics. The RNA binding protein DEAD-box helicase 3X-linked (DDX3X) was identified as a pivotal oncogene and biomechanical checkpoint. Specifically, DDX3X up-regulation in PDAC promoted tumorigenesis and metastasis, primarily through the transcriptional repressor TLE family member 2 (TLE2). Dysregulation of DDX3X in the tumor destabilized TLE2 messenger RNA and therefore disrupted the interaction with KLF4 (KLF transcription factor 4), leading to increased expression of myosin light chain 9 (MYL9). This change remodeled F-actin, enhancing tumor cell traction forces and consequently facilitating tumor metastasis. Targeting the DDX3X-TLE2-MYL9 pathway considerably reduces PDAC progression. This research reveals a promising approach for treating PDAC by focusing on biomechanical cues.<\/jats:p>","DOI":"10.1126\/sciadv.adw9519","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T17:58:34Z","timestamp":1757699914000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":7,"title":["RNA binding protein DDX3X drives pancreatic cancer progression via the TLE2-MYL9 axis"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1898-7897","authenticated-orcid":true,"given":"Yuanyang","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, 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