Biology subjects

Yu, J. S.

Publications and source records attributed to Yu, J. S..

3 recordsLinked to original sources

bioRxiv2021

HAUSP Stabilizes SOX2 through Deubiquitination to Maintain Self-renewal and Tumorigenic Potential of Glioma Stem Cells

Glioblastoma (GBM) is the most lethal brain tumor containing glioma stem cells (GSCs) that promote malignant growth and therapeutic resistance. The self-renewal and tumorigenic potential of GSCs are maintained by core stem cell transcription factors including SOX2. Defining the posttranslational regulation of SOX2 may offer new insights into GSC biology and potential therapeutic opportunity. Here, we discover that HAUSP stabilizes SOX2 through deubiquitination to maintain GSC self-renewal and tumorigenic potential. HAUSP is preferentially expressed in GSCs in perivascular niches in GBMs. Disrupting HAUSP by shRNA or its inhibitor P22077 promoted SOX2 degradation, induced GSC differentiation, impaired GSC tumorigenic potential, and suppressed GBM tumor growth. Importantly, pharmacological inhibition of HAUSP synergized with radiation to inhibit GBM growth and extended animal survival, indicating that targeting HAUSP may overcome GSC-mediated radioresistance. Our findings reveal an unappreciated crucial role of HAUSP in the GSC maintenance and provide a promising target for developing effective anti-GSC therapeutics to improve GBM treatment. HighlightsO_LIHAUSP deubiquitinates and stabilizes SOX2 in glioma stem cells (GSCs). C_LIO_LIHAUSP is preferentially expressed by GSCs in perivascular niches in GBMs. C_LIO_LIHAUSP is required for maintaining GSC self-renewal and tumorigenic potential. C_LIO_LITargeting HAUSP inhibited malignant growth in GSC-derived GBM xenografts. C_LIO_LIInhibition of HAUSP synergized with radiation to suppress GBM tumor growth. C_LI

cancer biology↗

bioRxiv2021

A Novel Non-Invasive Epithelial Ovarian Cancer Mouse Model Of Hyperthermic Intraperitoneal Chemotherapy (HIPEC)

BackgroundHyperthermic intraperitoneal chemotherapy (HIPEC) in combination with interval cytoreductive surgery increases the overall survival of epithelial ovarian cancer (EOC) patients with advanced disease. Despite its proven benefits, the mechanism by which HIPEC extends overall survival remains unknown and current strategies to optimize HIPEC are therefore limited. A major challenge is the lack of a robust and streamlined model to investigate the mechanisms underlying HIPEC efficacy. ObjectiveTo introduce a novel murine model that can be used to enhance our understanding of HIPEC therapy. MethodID8-luc, an EOC mouse cell line, is inoculated into immunocompetent C57BL/6J mice intraperitoneally. Once tumor is detected by In Vivo Imaging System (IVIS), cisplatin (5 mg/kg) is injected intraperitoneally and superficial hyperthermia of 40{degrees}C is applied to the animals abdomen and pelvis using an FDA-approved hyperthermia unit (BSD500) for 20 minutes. To validate the model, four treatment conditions were tested: cisplatin and hyperthermia, cisplatin and normothermia, vehicle and hyperthermia, and vehicle and normothermia. Tumor growth was assessed over the course of treatment using IVIS optical spectrum. ResultsTumor growth in mice treated with hyperthermic cisplatin was significantly suppressed compared to mice treated with normothermic cisplatin (p < 0.05). No significant differences in tumor growth were observed in the hyperthermic vehicle and normothermic vehicle groups. ConclusionsWe developed an innovative noninvasive mouse model of HIPEC. Similar to patients with advanced ovarian cancer who are treated with HIPEC at the time of interval cytoreductive surgery, our model demonstrates that hyperthermia enhances the inhibitory effect of cisplatin on intraperitoneal tumor growth. Development of this murine model provides an opportunity to elucidate the mechanisms underlying HIPEC and offer an opportunity to test adjunct treatments in a pre-clinical setting to enhance the utility of HIPEC.

cancer biology↗

bioRxiv2021

Resolving the Interactions Between Class 3 Semaphorin Receptors in Live Cells

The plexin/neuropilin/semaphorin family of proteins is involved with tissue patterning in the developing embryo. These proteins play roles in cell migration and adhesion, but are also important in disease, including cancer angiogenesis and metastasis. While some structures of the soluble domains of these proteins have been determined, the conformations of full-length receptor complexes are just beginning to be studied, especially within the context of the cell plasma membrane. Pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS) allows direct insight to the formation of protein-protein interactions in the membrane of live cells. Here we investigated the homodimerization of neuropilin-1, Plexin A2, Plexin A4, and Plexin D1. Consistent with previous studies, we found that neuropilin-1, Plexin A2 and Plexin A4 are dimers in the absence of exogenous ligand. Plexin D1, on the other hand, was monomeric under similar conditions, which had not been previously reported. We also found that Plexin A2 and A4 assemble into a heteromeric complex. Stimulation with Semaphorin 3A or Semaphorin 3C ligand neither disrupts nor enhances the dimerization of the receptors when they are expressed alone, suggesting that activation involves a conformational change rather than a shift in the monomer-dimer equilibrium. However, upon stimulation with Semaphorin 3C, Plexin D1 and neuropilin-1 form a heteromeric complex, while Semaphorin 3A does not induce a stable complex with these receptors. This analysis of interactions by PIE-FCCS provides a complementary approach to the existing structural and biochemical data that will aid in the development of new therapeutic strategies to target these receptors during disease.

biophysics↗