Elucidation of the Biosynthetic Process of Hyaluronan

There are an increasing number of bedridden elderly people in Japan with a loss of joint function due to conditions like osteoarthritis. Hyaluronan (HA) acts as a cushion and lubricant in articulating joints. It is an integral component of the synovial fluid between joints, but becomes reduced by age and thereby causes functional disorders. HA is a high molecular-mass polysaccharide found in the extracellular matrix, especially of that of connective tissues, and is composed of repeating disaccharide units in which N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) are linked together by alternating ß-1,3 and ß-1,4 linkages. Our laboratory discovered the first mammalian HA synthase (HAS) gene and has been thoroughly investigating the mechanism of HA biosynthesis ever since. Recently, we succeeded in establishing an in vitro reconstitutionsystem using a recombinant HAS protein and developed a screening system for compounds that have HAS activation potential. Our future challenge is therefore to understand the entire mechanism of HA biosynthesis and apply this knowledge to developing innovative anti-aging technologies.

Studies on the Regulation of Cancer Stemness

Our previous studies using a mammary tumor mouse model demonstrated that HA overproduction promotes cancer stemness. Because excess HA production consumes large quantities of the cytosolic nucleotide sugars as substrates, overproduction of this polysaccharide may alter networks for the cellular metabolism. We adopted stable isotope-assisted tracing and mass spectrometry profiling to elucidate the metabolic features of HA-overproducing breast cancer cells. These integrated approaches disclosed an acceleration of metabolic flux in the hexosamine biosynthetic pathway. A metabolic shift toward glycolysis and simultaneous accumulation of HIF-1α were also evident in HA-overproducing cancer cells. Therefore, we are currently investigating whether HA production regulates the CSC-like properties of breast cancer cells via HBP-coupled HIF-1 signaling.

Studies on CSC Niches

Cancer has become the leading cause of death in our country due to increased longevity, and as such the eradication of cancer has become a social mission. Although it is well known that uncontrolled cell proliferation leads to the development of cancers, the precise mechanisms underlying metastatic tumor progression and recurrence have not been fully resolved. Cancer stem cells (CSCs) have recently been reported to exist in many malignancies and have attracted remarkable attention because they are believed to be the only cells capable of initiating cancer growth. Because CSCs are relatively resistant to conventional chemotherapy and radiotherapy, and because they are closely associated with cancer metastasis and recurrence, targeting them is now a primary goal in cancer therapy.
CSCs, like normal stem cells, reside and maintain their stemness within a specialized microenvironment called a stem cell niche. Thus, strategies to limit their stemness and malignant transformation must focus on the importance of targeting this CSC niche. The main purpose of our research in this domain is to identify the cellular and molecular cues that govern the formation of the specialized CSC niche microenvironment and establish novel therapies to induce a state of cancer dormancy by controlling the niche.

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