Hyaluronan catabolism supports the peritoneal disseminated metastasis of cancer through the glucuronic acid pathway

When disseminated into the peritoneal cavity at the very early stage, cancer cells must adapt to the glucose- and oxygen-limited environment in peritoneal fluid. To investigate the molecular mechanisms enabling this adaptation, we conducted a genome-wide CRISPR/Cas9 knockout screening in an orthotopic ovarian cancer (OC) model. We identified a series of genes involved in hyaluronic acid (HA) catabolism and glucuronic acid (GlcA) metabolism, including the HA receptor LAYN, HA catabolism enzymes (including HYAL1 and HYAL3) and key GlcA metabolic enzymes (such as AKR1A1 and XYLB). By integrating transcriptomic and metabolic analyses in multiple experimental systems, we demonstrated that HA induced the expression of key HA catabolism and GlcA pathway enzymes, which further led to the release of free GlcA from HA degradation. This GlcA is subsequently metabolized through the GlcA pathway, the pentose phosphate pathway (PPP) and glycolysis to support the maintenance and growth of disseminated OC cells. In addition, we found an atypical Rho GTPase RHOU facilitated the LAYN endosomal recycling for efficient HA uptake. Intriguingly, the rewiring of HA catabolism through GlcA pathway was regulated by its classical receptor CD44 and occurred in other peritoneal disseminating cancers such as bladder cancer and pancreatic adenocarcinoma. Importantly, pharmacological inhibition of HYAL1 with garcinol potently suppressed peritoneal disseminated metastasis in xenograft mice and synergized with cisplatin. In this study, we collectively reported a novel metabolic reprogramming feature of the early peritoneal disseminated cancer cells, which provides new diagnostic and therapeutic strategies for the cancers prone to the potential dissemination.