Hyaluronic acid is a master regulator of tumor stroma
Juan Rodríguez Vita
Centro de Investigación Príncipe Felipe, Valencia [Spain]
Tumor cells use signals to communicate and educate the tumor stroma. These signals are often present in the extracellular matrix (ECM). I will show you how tumor cells take advantage of one of the components of this ECM, hyaluronic acid (HA) to modify their stroma in order to generate a more immunosuppressive environment and increase their metastatic potential. HA can be synthesized as low molecular mass-HA (LMM-HA) or high molecular mass-HA (HMM-HA). Firstly, I will describe how HMM-HA produced by ovarian cancer cells, when recognized by macrophages, depletes membrane cholesterol from their plasma membranes. Cholesterol depletion alters IL-4 signaling and amplifies its responses. This led as to study the role of HA in Pancreatic ductal adenocarcinoma (PDAC) where ECM can make up to 90 % of the desmoplastic tumor mass and HA is one if its main components. We found that Hyaluronan and proteoglycan link protein 1 (HAPLN1) which is crosslinks HA with other proteoglycan is an important regulator of HA actions. We found that HAPLN1 induces a Hyperplastic phenotype in tumor cells. HAPLN1 induces the reorganization of the ECM by upregulation of HMM-HA through the upregulation of HAS2. The action of HAPLN1 on tumor cells and CAFs promotes an immune-modulatory microenvironment that favors disease progression in vivo.