Science news

Cancer Cell: A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations (Zhang et al.) – an important contribution to the cancer literature; this study takes advantage of the recent completion of the data generation stage of the The Cancer Genoem Atlas (TCGA) and performs a systematic analysis of the PI3K/AKT/mTOR pathway in over 10,000 cancer, covering 32 different major cancer types. It examines mutated genes via whole-exome/genome sequencing, transcriptomics data (RNAseq) and candidate signalling data with reverse-phase protein arrays. It is a data-dense study, but I will just highlight a few points that were interesting to me. Although activities in the PI3K/AKT and mTOR pathways were highly correlated in multiple cancer, there were also instances with evidence for some decoupling. Moreover, this study provides some high-throughput functional characterisation of a larger set of activating PIK3CA mutations in two different immortalised cell lines; one caveat with this functional analysis, however, is the fact that it relies on overexpression of the mutated proteins. Nevertheless, as the setting is the same for all tested variants, it allows for direct comparisons among them to be made – and such comparisons are quite useful as there is very limited data on the functional significance of different PIK3CA mutations beyond the well-known hotspot variants. Overall, the large sample size used to generate this data provides substantial power to detect meaningful patterns that can be used to stratify variants in the clinical setting.

Nature: TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling (Wang et al.) – a key paper and really worth a read (or at least of key points as it is quite data dense!!). Probably one of the most comprehensive papers on mTORC2 that I have seen that also links it to relevant (patho)physiology. Very interesting that growth factors (incl. insulin) tip the balance between mTORC2 and mTORC1 formation, favouring mTORC2 which then drives increased AKT activation. Evidence provided that this is relevant in conditions of PI3K/AKT hyperactivation. Very interesting!! Also, noted that they use HEK293s in multiple experiments and manage to look at PI3K/AKT signalling after serum starving these for 16h.. Usually these cells exhibit hyperactivation of this pathway, but the control conditions here show no sign of this?

Science: A subcellular map of the human proteome (Thul et al.) – an important atlas-like resource, essentially an image-based map of the subcellular proteome based on transcriptomics, immunofluorescence and mass spectrometry. It is quite impressive, the data covers 12,0003 proteins using a panel of 22 human cell lines and 13,993 antibodies. Also, they have managed to get the images annotated through a Citizen Science approach via massive multiplayer game with participation from over 180,000 worldwide players! This dataset is actually quite important as it allows for more refined interaction networks to be constructed. The interactive resources can be accessed here: http://www.proteinatlas.org

Science: ATP as a biological hydrotrope (Patel et al.) – haven’t read beyond abstract, but interesting because it seems to suggest a role for ATP in protein solubilisation within cells. (Hydrotorope = amphiphilic molecules with low cooperativity and millimolar working concentrations, differentiating them from surfactants ➡ act to solubilise hydrophobic molecules in acqueous solutions).

Science Signalling: p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM (Stewart-Ornstein, J. and Lahav, G.) ➡ this study highlights an issue that is worth keeping in mind whenever a cell biology paper is examined: signalling dynamics do differ across cell lines, hence using a single cell lines as model system for a major phenomenon might not yield results that are broadly applicable. This paper has also got some mathematical modelling for those interested in that. I must admit that I have not read it in much detail and I am unable to comment on the computational approach.

Diabetes: Mechanisms of Insulin Resistance in Primary and Secondary Non-Alcoholic Fatty Liver (Jelenik et al.) ➡ can’t usually access, but here is the abstract:

“Non-alcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose-tissue lipolysis (SEC). We studied mice with hepatocyte- or adipocyte-specific sterol regulatory-element binding protein-1c (SREBP-1c) overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol (DAG) content and protein kinase C (PKC)ε translocation. SEC mice had decreased hepatic ChREBP-mediated lipogenesis and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis, only if adipose tissue lipid storage capacity is preserved.”

Nature Cell Biology Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling (Jin et al.)

Cell Reports: Widespread Mitotic Bookmarking by Histone Marks and Transcription Factors in Pluripotent Stem Cells (Liu et al.) – interesting paper that demonstrates that one of the mechanisms whereby the core stemness factor OCT4 maintains pluripotency is by bookmarking stemness genes during mitosis, i.e. a memory mechanisms that allows for re-expression of these genes when mitosis is completed. This is important in stem cells due to their unusual cell cycle characteristics (10-12h cycling, no G0 phase and very short G1 phase). I find one of their approaches quite cool – testing the effect of specifically degrading OCT4 during mitosis by fusing OCT4 to a Cyclin destruction box.

Nature Protocols: FISH-Flow, a protocol for the concurrent detection of mRNA and protein in single cells using fluorescence in situ hybridization and flow cytometry (Arrigucci et al.) note that this is only applicable for non-adherent cell types at the moment)

eLife: Addressing the ethical issues raised by synthetic human entities with embryo-like features (Aach et al.) – interesting read, I think…

 

 

 

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