Citations 2
Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis
Khanal, Shalil , Liu, Yuanhang , Wixom, Alexander Q. , Washington, Alexander M. , Jalan‐Sakrikar, Nidhi , Cooper, Shawna A. , Vučković, Ivan , Zhang, Song , Zhong, Jun , Johnson, Kenneth L. , Charlesworth, M. Cristine , Kim, I.Y. , Yeon, Yubin, Yoon, Sangwoong , Noh, Yung‐Kyun , Meroueh, Chady , Timbilla, Abdul Aziz , Yaqoob, Usman , Gao, Jinhang , Kim, Yohan , Hay, Nissim , Shah, Vijay H. , Bamidele, Adebowale O , Wixom, Alexander Q , Washington, Alexander M , Sakrikar, Nidhi Jalan , Cooper, Shawna A , Vuckovic, Ivan , Zhang, Song , Zhong, Jun , Johnson, Kenneth , Kim, Iljung , Yeon, Yubin , Yoon, Sangwoong , Noh, Yung-Kyun , Meroueh, Chady , Timbilla, Abdul Aziz , Gao, Jinhang , Kim, Yo Han , Lucien, Fabrice , Simons, Michael , Shah, Vijay H , Kostallari, Enis , Liu, Yuanhang, Bamidele, Adebowale O. , Charlesworth, M. Cristine , Yaqoob, Usman , Lucien, Fabrice , Huebert, Robert C. , Simons, Michael , Kostallari, Enis
Science Advances | June 28, 2024 | Volume: 10 | Issue: 26 | Pages: No page available
Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nanosized extracellular vesicles (EVs), and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated up-regulation of EV-related pathways in the liver pericentral zone, which was abrogated by glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs up-regulated the expression of EV-related genes such as Ras-related protein Rab-31 ( RAB31 ) by enhancing histone 3 lysine 9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
Combined Antitumor Effect of the Serine Protease Urokinase Inhibitor Upamostat and the Sphingosine Kinase 2 Inhibitor Opaganib on Cholangiocarcinoma Patient-Derived Xenografts
Asumda, Faizal Z., Campbell, Nellie A. , Hassan, Mohamed A. , Fathi, Reza , Rico, Daniella F. Vasquez, Kiem, Melanie, Vang, Ethan V., Kim, Yo Han , O’Brien, Daniel R. , Buhrow, Sarah A. , Ben-Yair, Vered Katz , Levitt, Mark L. , Leiting, Jennifer L. , Abdelrahman, Amro M. , Zhu, Xinli, Lucien, Fabrice , Truty, Mark J. , Roberts, Lewis R. , O'Brien, Daniel R, Levitt, Mark L , Abdelrahman, Amro M , Lucien, Fabrice , Roberts, Lewis R , Campbell, Nellie A , Luo, Xin , Reid, Joel M. , Moore, Michael J.
Cancers | March 5, 2024 | Volume: 16 | Issue: 5 | Pages: 1050
Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.