Targeted Depletion of Hyaluronic Acid Mitigates Murine Breast Cancer Growth

SIMPLE SUMMARY: Breast cancer often contains excessive stromal matrix components that serve as a barrier to therapy. One such component is hyaluronic acid (HA), which also plays important roles in tumor progression and spread. In this study, we engineered an attenuated Salmonella typhimurium secreting a bacterial hyaluronidase (YS-HAse) and show that it degrades HA within murine breast tumors, resulting in enhanced tumor permeability and growth control. YS-HAse represents a promising new therapeutic approach that could also be used alongside current treatments to improve their delivery and effectiveness. ABSTRACT: Hyaluronic acid (HA) is highly elevated in breast cancers compared to normal breast tissue and is associated with increased tumor aggressiveness and poor prognosis. HA interacts with cell-trafficking CD44 receptors to promote tumor cell migration and proliferation and regulates both pro- and anti-inflammatory cytokine production through tumor-associated macrophages. The highly negative charge of HA enables its uptake of vast amounts of water that greatly increases the tumor interstitial fluidic pressure, which, combined with the presence of other extracellular matrix components such as collagen, results in tumor stroma with abnormal vasculature, hypoxia, and increased drug resistance. Thus, the degradation of HA in breast cancer may attenuate growth and improve permeability to anticancer agents. Previous methods to deplete tumor HA have resulted in significant off-tumor effects due to the systemic use of mammalian hyaluronidases. To overcome this, we developed a hyaluronidase-secreting Salmonella typhimurium (YS-HAse) that specifically and preferentially colonizes tumors to deplete HA. We show that the systemic administration of YS-HAse in immunocompetent murine models of breast cancer enhances tumor perfusion, controls tumor growth, and restructures the tumor immune contexture. These studies highlight the utility of YS-HAse as a novel microbial-based therapeutic that may also be combined with existing therapeutic approaches.