Targeting Asparagine Metabolism in Well-Differentiated/Dedifferentiated Liposarcoma

BackgroundmTORC1 activity is dependent on the presence of micronutrients, including Asparagine (Asn), to promote anabolic cell signaling in many cancers. We hypothesized that targeting Asn metabolism would inhibit tumor growth by reducing mTORC1 activity in well-differentiated (WD)/dedifferentiated (DD) liposarcoma (LPS).MethodsHuman tumor metabolomic analysis was utilized to compare abundance of Asn in WD vs. DD LPS. Gene set enrichment analysis (GSEA) compared relative expression among metabolic pathways upregulated in DD vs. WD LPS. Proliferation assays were performed for LPS cell lines and organoid models by using the combination treatment of electron transport chain (ETC) inhibitors with Asn-free media. 13C-Glucose-labeling metabolomics evaluated the effects of combination treatment on nucleotide synthesis. Murine xenograft models were used to assess the effects of ETC inhibition combined with PEGylated L-Asparaginase (PEG-Asnase) on tumor growth and mTORC1 signaling.ResultsAsn was enriched in DD LPS compared to WD LPS. GSEA indicated that mTORC1 signaling was upregulated in DD LPS. Within available LPS cell lines and organoid models, the combination of ETC inhibition with Asn-free media resulted in reduced cell proliferation. Combination treatment inhibited nucleotide synthesis and promoted cell cycle arrest. In vivo, the combination of ETC inhibition with PEG-Asnase restricted tumor growth.ConclusionsAsn enrichment and mTORC1 upregulation are important factors contributing to WD/DD LPS tumor progression. Effective targeting strategies require limiting access to extracellular Asn and inhibition of de novo synthesis mechanisms. The combination of PEG-Asnase with ETC inhibition is an effective therapy to restrict tumor growth in WD/DD LPS

Tracking submarine volcanic activity at Monowai: Constraints from long-range hydroacoustic measurements

Monowai is a submarine volcanic center in the Kermadec Arc, Southwest Pacific Ocean. In the past, activity at the volcano had been intermittently observed in the form of fallout at the sea surface, discolored water, changes in seafloor topography, and T phase seismicity, but there is no continuous record for more recent years. In this study, we investigated 3.5 years of recordings at a hydrophone array of the International Monitoring System (IMS), located near Juan Fernández Islands for long‐range underwater sound waves from Monowai. Results from direction‐of‐arrival calculations and density‐based spatial clustering indicate that 82 discrete episodes of activity occurred between July 2003 and March 2004, and from April 2014 to January 2017. Volcanic episodes are typically spaced days to weeks apart, range from hours to days in length, and amount to a cumulative sum of 137 days of arrivals in total, making Monowai one of the most active submarine arc volcanoes on Earth. The resolution of the hydrophone recordings surpasses broadband network data by at least one order of magnitude, identifying seismic events as low as 2.2 mb in the Kermadec Arc region. Further observations suggest volcanic activity at a location approximately 400 km north of Monowai in the Tonga Arc, and at Healy or Brothers volcano in the southern Kermadec Arc. Our findings are consistent with previous studies and highlight the exceptional capabilities of the IMS network for the scientific study of active volcanism in the global ocean. Supporting Informatio

Fibroblast Activation Protein Expression in Sarcomas.

ObjectivesFibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas.MethodsAvailable tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, <25%, 25-75%; >75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168).ResultsThe majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression.ConclusionThe majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted