Abstract A009: CEMIP-Mediated hyaluronic acid metabolism Drives PDAC Metastasis
Hee Seung LeeAbstract
Background:
Pancreatic ductal adenocarcinoma (PDAC) exhibits a highly desmoplastic microenvironment enriched with hyaluronan (HA). Degradation of high-molecular-weight HA into low-molecular-weight HA (LMW-HA) generates bioactive fragments that promote cancer cell plasticity, migration, and invasion. However, the contribution of HA fragmentation to PDAC metastasis remains poorly defined.
Methods:
We analyzed HA accumulation in orthotopic mouse model and the expression of HA-related genes in PDAC cell lines. The GAG-related pathway using pseudo-bulk RNA analysis, and GSEA. The expression of CEMIP, a key enzyme in HA degradation, was evaluated in metastatic versus non-metastatic samples. Furthermore, LMW-HA-mediated alteration of EMT markers and PDAC cells invasion or migration were compared with the control groups.
Results:
The expression of HA-synthesis genes was increased in PDAC cell lines compared to normal pancreatic cell line, alongside robust HA accumulation in primary stroma and metastatic liver sites. Meta-analysis and experimental data showed that CEMIP expression is significantly elevated in metastatic tumors compared to primary non-metastatic samples. High CEMIP expression correlated with decreased overall survival and increased metastatic penetrance. Knockdown of CEMIP effectively inhibited the breakdown of HMW-HA into LMW-HA. Crucially, treatment with LMW-HA directly stimulated the migration and invasion of PDAC cells and upregulated key receptors such as RHAMM and TLR2, while these effects occurred independently of changes in EMT markers.
Conclusions:
Our findings establish CEMIP as a key regulator of the PDAC metastatic niche through its role in hyaluronan metabolism. By fragmenting HMW-HA, CEMIP orchestrates a transition in the extracellular matrix that activates RHAMM- and TLR2-dependent signaling, driving migration and invasion without requiring EMT. These results suggest that modulating the LMW-HA production via the CEMIP/HMW-HA axis is a potent therapeutic approach to impede the structural and signaling cues that facilitate systemic dissemination in pancreatic cancer.
Citation Format:
Hee Seung Lee. CEMIP-Mediated hyaluronic acid metabolism Drives PDAC Metastasis [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A009.