Biology subjects

Trasanidis, N.

Publications and source records attributed to Trasanidis, N..

3 recordsLinked to original sources

bioRxiv2020

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma

ZBP1 is an inducible, non-constitutively expressed cellular nucleic acid sensor that triggers type I interferon (IFN) responses via phosphorylation and activation of the transcription factor (TF) IRF3 by TBK1. However, the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively and constitutively expressed in late B cell development and it is required for optimal T cell-dependent humoral immune responses. In the plasma cell (PC) cancer multiple myeloma, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. Notably, rather than IFN type I response genes, IRF3 directly activates, in part through co-operation with the PC lineage-defining TF IRF4, cell cycle genes thus promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. These data expand our knowledge of the role of cellular immune sensors in cancer biology.

cancer biology↗

bioRxiv2020

Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding

Vitellogenesis and oocyte maturation require anautogenous female Anopheles mosquitoes to obtain a bloodmeal from a vertebrate host. The bloodmeal is rich in proteins that are readily broken down into amino acids in the midgut lumen and absorbed by the midgut epithelial cells where they are converted into lipids and then transported to other tissues including ovaries. The stearoyl-CoA desaturase (SCD) plays a pivotal role in this process by converting saturated (SFAs) to unsaturated (UFAs) fatty acids; the latter being essential for maintaining cell membrane fluidity amongst other housekeeping functions. Here, we report the functional and phenotypic characterization of SCD1 in the malaria vector mosquito Anopheles coluzzii. We show that RNA interference (RNAi) silencing of SCD1 and administration of sterculic acid (SA), a small molecule inhibitor of SCD1, significantly impact on the survival and reproduction of female mosquitoes following blood feeding. Microscopic observations reveal that the mosquito thorax is quickly filled with blood, a phenomenon likely caused by the collapse of midgut epithelial cell membranes, and that epithelial cells are depleted of lipid droplets and oocytes fail to mature. Transcriptional profiling shows that genes involved in protein, lipid and carbohydrate metabolism and immunity-related genes are the most affected by SCD1 knock down (KD) in blood-fed mosquitoes. Metabolic profiling reveals that these mosquitoes exhibit increased amounts of saturated fatty acids and TCA cycle intermediates, highlighting the biochemical framework by which the SCD1 KD phenotype manifests as a result of a detrimental metabolic syndrome. Accumulation of SFAs is also the likely cause of the potent immune response observed in the absence of infection, which resembles an auto-inflammatory condition. These data provide insights into mosquito bloodmeal metabolism and lipid homeostasis and could inform efforts to develop novel interventions against mosquito-borne diseases.

microbiology↗

bioRxiv2020

Over-accessible chromatin links myeloma initiating genetic events to oncogenic transcriptomes and aberrant transcription factor regulatory networks

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Myeloma initiating genetic events define subgroups (MIE) and drive distinct oncogenic transcriptomes that converge into a mutually exclusive overexpression of CCND1 and CCND2 oncogenes. Here, with reference to normal PC, we dissect how MIE impact the chromatin regulatory landscape of MM. We find that chromatin accessibility combined with transcriptome profiling classifies myeloma genetic subgroups, while in a topologically constrained manner, distal rather than proximal regulatory elements influence myeloma transcriptomes. Across and within MIE-defined subgroups, genes and pathways critical for myeloma biology can be linked to developmentally activated or de novo formed enhancers. We show that existing transcription factors, co-opted to organise highly ordered, aberrant regulatory networks, generate known and novel myeloma cell dependencies and help identify prognostic markers. Finally, we discover and functionally validate the critical enhancer that regulates ectopic expression of CCND2 in MM.

cancer biology↗