CEMIP2 sensitizes PDAC to chemotherapy through extracellular matrix remodeling by hyaluronan degradation

Pancreatic ductal adenocarcinoma (PDAC) ranks as third leading cause of cancer-related mortality, with chemoresistance progression driven by the desmoplastic extracellular matrix (ECM). Hyaluronic acid (HA), one of the major components of ECM, is notably enriched in PDAC. HA-based strategies, like lowering HA levels with a hyaluronidase, are worthy of experimental evidence for PDAC. Our previous work identified CEMIP2 (Cell migration inducing hyaluronidase 2) as a proteomic biomarker predictive of adjuvant chemotherapy response in PDAC, though its mechanistic role remains unclear. Herein, we observed that elevated CEMIP2 expression correlates with improved patient response to neoadjuvant and adjuvant chemotherapy. Using PDAC murine models, we reveal that CEMIP2 enhances gemcitabine efficacy through HA-dependent mechanisms involving drug delivery potentiation and vascular density modulation, attributable to its HA-degrading capacity. Consistent with this, CEMIP2 expression shows an inverse correlation with HA levels in clinical PDAC specimens, while low HA levels themselves associate with favorable treatment response and survival outcomes. Single-cell RNA sequencing (scRNA-seq) uncovered that CEMIP2 knockdown alters the tumor microenvironment (TME) by expanding cancer-associated fibroblast (CAF) populations. Both inflammatory (iCAF) and myofibroblast (myCAF) subtypes exhibited SPP1-CD44-mediated crosstalk with PDAC cells. Additionally, cytometry by time-of-flight (CyTOF) revealed that CEMIP2 depletion modulates the abundance and functional states of immune subsets, particularly tumor-associated macrophages (TAMs) and T cell populations. Collectively, our findings establish CEMIP2 as a critical regulator of chemotherapy response that reprograms the TME through HA degradation and ECM remodeling, providing novel insights into PDAC treatment resistance mechanisms.