Science advancesSep 12, 2025

RNA-binding protein DDX3X may promote pancreatic cancer growth through the TLE2-MYL9 pathway

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

DDX3X may promote pancreatic cancer growth and metastasis through a TLE2-MYL9 biomechanical pathway.

Evidence

A CRISPR-Cas9 screen and mechanistic orthotopic xenograft PDAC experiments linked DDX3X up-regulation to TLE2 mRNA destabilization, MYL9 increase, F-actin remodeling, and higher tumor traction forces.

Caveat

The therapeutic claim remains preclinical because the evidence comes from xenograft and mechanistic models rather than human treatment outcomes.

Simplified

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.