Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.

A pilot study on the effects of S-equol compared to soy isoflavones on menopausal hot flash frequency.

BACKGROUND: S-equol, a metabolite of the soy isoflavone daidzein, has been proposed as having potential for relief of menopausal symptoms. This study compared the efficacy of the natural S-equol supplement, SE5-OH, with isoflavones for relieving hot flashes and other menopausal symptoms. METHODS: An 8-week randomized, double-blind, active comparator trial with SE5-OH was conducted in postmenopausal women (aged 45-65 years), who experienced ≥5 hot flashes/day. Participants (n=102) were assigned to one of four treatment groups: 10 (n=24), 20 (n=27), or 40 (n=25) mg S-equol/day or soy isoflavones (n=26). Participants recorded their hot flash frequency and rated their menopause symptom severity. RESULTS: Reductions in hot flash frequency at week 8 were similar for all treatment groups. However, based on analyses of the cumulative effect for the 8-week period, 40 mg/day S-equol had a greater reduction of hot flash frequency compared to isoflavones (p=0.021). A subgroup analysis further indicated that for subjects with >8 hot flashes/day at baseline, 20 and 40 mg/day S-equol were superior to isoflavones in reducing hot flash frequency (p=0.045 and p=0.001, respectively). In addition, 10 and 20 mg/day S-equol improved muscle and joint pain score compared with isoflavones (p=0.003 and p=0.005, respectively). CONCLUSIONS: S-equol, 10 mg/day, appears to be as effective as soy isoflavones at reducing hot flash frequency and more effective for relieving muscle and joint pain in postmenopausal women. S-equol, ≥20 mg/day, alleviates hot flashes to a greater extent than soy isoflavones in those women who experience >8 hot flashes/day.