Context-Dependent Spatial and Functional Roles of CD44 Across Pancreatic Ductal Adenocarcinoma States

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) comprises distinct cellular states characterized by different differentiation programs and therapeutic responses. How a cell-surface receptor adapts its function across these states remains poorly understood. Here, we investigated whether the spatial organization and functional output of CD44 vary across PDAC cellular states.

Methods

CD44 expression and spatial distribution were examined in human PDAC tissues and PDAC cell models representing different differentiation states. The functional roles of CD44 were investigated using genetic depletion, transcriptomic analysis, migration and invasion assays, and xenograft and orthotopic models. Hyaluronan (HA) responsiveness and downstream signaling were assessed following exogenous HA stimulation, and the therapeutic effects of HA synthesis inhibition with 4-methylumbelliferone (4-MU) were evaluated alone or in combination with gemcitabine.