Friday, August 30, 2019

Fly model of glioma used to identify potential therapeutic target

Chi KC, Tsai WC, Wu CL, Lin TY, Hueng DY. An Adult Drosophila Glioma Model for Studying Pathometabolic Pathways of Gliomagenesis. Mol Neurobiol. 2019 Jun;56(6):4589-4599. doi: 10.1007/s12035-018-1392-2. Epub 2018 Oct 24. PubMed PMID: 30357574.

Abstract: "Glioblastoma multiforme (GBM), the most prevalent brain tumor in adults, has extremely poor prognosis. Frequent genetic alterations that activate epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling, as well as metabolic remodeling, have been associated with gliomagenesis. To establish a whole-animal approach that can be used to readily identify individual pathometabolic signaling factors, we induced glioma formation in the adult Drosophila brain by activating the EGFR-PI3K pathway. Glioma-induced animals showed significantly enlarged brain volume, early locomotor abnormalities, memory deficits, and a shorter lifespan. Combining bioinformatics analysis and glial-specific gene knockdown in the adult fly glioma model, we identified four evolutionarily conserved metabolic genes, including ALDOA, ACAT1, ELOVL6, and LOX, that were involved in gliomagenesis. Silencing of ACAT1, which controls cholesterol homeostasis, reduced brain enlargement and increased the lifespan of the glioma-bearing flies. In GBM patients, ACAT1 is overexpressed and correlates with poor survival outcomes. Moreover, pharmacological inhibition of ACAT1 in human glioma cell lines revealed that it is essential for tumor proliferation. Collectively, these results imply that ACAT1 is a potential therapeutic target, and cholesterol homeostasis is strongly related to glioma formation. This in vivo model provides several rapid and robust phenotypic readouts, allowing determination of the pathometabolic pathways involved in gliomagenesis, as well as providing valuable information for novel therapeutic strategies."

Monday, August 19, 2019

Fly study reveals potential mechanism of male vs. female differences in cancer malignancy

The histone code reader PHD finger protein 7 controls sex-linked disparities in gene expression and malignancy in Drosophila

Cristina Molnar, Jan Peter Heinen, Jose Reina, Salud Llamazares, Emilio Palumbo, Alessandra Breschi, Marina Gay, Laura Villarreal, Marta Vilaseca, Giulia Pollarolo and Cayetano Gonzalez

Science Advances  14 Aug 2019:
Vol. 5, no. 8, eaaw7965
DOI: 10.1126/sciadv.aaw7965

Abstract: "The notable male predominance across many human cancer types remains unexplained. Here, we show that Drosophila l(3)mbt brain tumors are more invasive and develop as malignant neoplasms more often in males than in females. By quantitative proteomics, we have identified a signature of proteins that are differentially expressed between male and female tumor samples. Prominent among them is the conserved chromatin reader PHD finger protein 7 (Phf7). We show that Phf7 depletion reduces sex-dependent differences in gene expression and suppresses the enhanced malignant traits of male tumors. Our results identify potential regulators of sex-linked tumor dimorphism and show that these genes may serve as targets to suppress sex-linked malignant traits."

Flies used to test drug activity predicted using dynamic combinatorial chemistry approach

Canal-Martín A, Sastre J, Sánchez-Barrena MJ, Canales A, Baldominos S, Pascual N, Martínez-González L, Molero D, Fernández-Valle ME, Sáez E, Blanco-Gabella P, Gómez-Rubio E, Martín-Santamaría S, Sáiz A, Mansilla A, Cañada FJ, Jiménez-Barbero J, Martínez A, Pérez-Fernández R. Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library. Nat Commun. 2019 Jun 26;10(1):2798. PMID: 31243268; PMCID: PMC6595003.

Abstract: "Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations."