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.
Keywords: Streptomyces koganeinsis; attenuated Salmonella typhimurium; bacterial hyaluronidase; breast cancer; delivery; desmoplasia; drug resistance; hyaluronan; hyaluronic acid.