Interaction between m6A and YAP1 mechanotransduction pathways is essential for mechanical memory and matrix remodeling in pancreatic cancer

TL;DR

This study reveals how pancreatic cancer cells remember mechanical environments, leading to stiffer tumors and worse outcomes.

Contribution

The discovery of a METTL14-YAP1 feedback loop that regulates mechanical memory and stromal remodeling in pancreatic cancer.

Findings

A high-stiffness environment induces mechanical memory in pancreatic cancer cells.

The METTL14-YAP1 feedback loop regulates mechanical memory through m6A-dependent translation.

This loop activates CD166-EGFR-LOXL2 signaling, increasing stromal stiffness and tumor stemness.

Abstract

Pancreatic cancer is a highly aggressive malignancy characterized by a progressively stiffened extracellular matrix, which promotes mechanical memory acquisition in cancer cells and facilitates malignant progression and metastasis. Despite its clinical significance, the mechanisms underlying matrix stiffening and mechanical memory formation remain poorly defined. This study demonstrates that a high-stiffness microenvironment induces mechanical memory in pancreatic tumor cells, which in further aggravates stromal remodeling and adversely affects prognosis. Under mechanically stiff conditions, pancreatic cancer cells exhibit pronounced enrichment of RNA modification-related and metabolic pathways, along with significantly increased m6A levels. Mechanistically, METTL14 enhances YAP1 expression through YTHDF3-mediated m6A-dependent translational regulation, while YAP1 in turn transcriptionally upregulates METTL14 via TEAD1, establishing a positive feedback loop that sustains mechanical memory. This METTL14-YAP1 axis activates CD166-EGFR-LOXL2 signaling, leading to enhanced collagen cross-linking and deposition, increased stromal stiffness, and maintenance of tumor stemness. These results identify the METTL14-YAP1 feedback loop as a core regulator of mechanical memory in pancreatic ductal adenocarcinoma, which drives stromal dysfunction and tumor progression through CD166-LOXL2 axis, and suggest targeting this loop as a potential therapeutic strategy to disrupt mechanical memory and ameliorate stiffness-induced remodeling.

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