3D Growth of Cancer Cells Elicits Sensitivity to Kinase Inhibitors but Not Lipid Metabolism Modifiers

Tumor cells exhibit altered lipid metabolism compared with normal cells. Cell signaling kinases are important for regulating lipid synthesis and energy storage. How upstream kinases regulate lipid content, versus direct targeting of lipid-metabolizing enzymes, is currently unexplored. We evaluated intracellular lipid concentrations in prostate and breast tumor spheroids, treated with drugs directly inhibiting metabolic enzymes fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), diacylglyceride acyltransferase (DGAT), and pyruvate dehydrogenase kinase (PDHK), or cell signaling kinase enzymes PI3K, AKT, and mTOR with lipidomic analysis. We assessed whether baseline lipid profiles corresponded to inhibitors' effectiveness in modulating lipid profiles in three-dimensional (3D) growth and their relationship to therapeutic activity. Inhibitors against PI3K, AKT, and mTOR significantly inhibited MDA-MB-468 and PC3 cell growth in two-dimensional (2D) and 3D spheroid growth, while moderately altering lipid content. Conversely, metabolism inhibitors against FASN and DGAT altered lipid content most effectively, while only moderately inhibiting growth compared with kinase inhibitors. The FASN and ACC inhibitors' effectiveness in MDA-MB-468, versus PC3, suggested the former depended more on synthesis, whereas the latter may salvage lipids. Although baseline lipid profiles did not predict growth effects, lipid changes on therapy matched the growth effects of FASN and DGAT inhibitors. Several phospholipids, including phosphatidylcholine, were also upregulated following treatment, possibly via the Kennedy pathway. As this promotes tumor growth, combination studies should include drugs targeting it. Two-dimensional drug screening may miss important metabolism inhibitors or underestimate their potency. Clinical studies should consider serial measurements of tumor lipids to prove target modulation. Pretherapy tumor classification by de novo lipid synthesis versus uptake may help demonstrate efficacy

EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2.

Accurate DNA replication is essential to preserve genomic integrity and prevent chromosomal instability-associated diseases including cancer. Key to this process is the cells' ability to stabilize and restart stalled replication forks. Here, we show that the EXD2 nuclease is essential to this process. EXD2 recruitment to stressed forks suppresses their degradation by restraining excessive fork regression. Accordingly, EXD2 deficiency leads to fork collapse, hypersensitivity to replication inhibitors, and genomic instability. Impeding fork regression by inactivation of SMARCAL1 or removal of RECQ1's inhibition in EXD2-/- cells restores efficient fork restart and genome stability. Moreover, purified EXD2 efficiently processes substrates mimicking regressed forks. Thus, this work identifies a mechanism underpinned by EXD2's nuclease activity, by which cells balance fork regression with fork restoration to maintain genome stability. Interestingly, from a clinical perspective, we discover that EXD2's depletion is synthetic lethal with mutations in BRCA1/2, implying a non-redundant role in replication fork protection

Galaxy Zoo: Are Bars Responsible for the Feeding of Active Galactic Nuclei at 0.2 < z < 1.0?

We present a new study investigating whether active galactic nuclei (AGN) beyond the local universe are preferentially fed via large-scale bars. Our investigation combines data from Chandra and Galaxy Zoo: Hubble (GZH) in the AEGIS, COSMOS, and GOODS-S surveys to create samples of face-on, disc galaxies at 0.2 < z < 1.0. We use a novel method to robustly compare a sample of 120 AGN host galaxies, defined to have 10^42 erg/s < L_X < 10^44 erg/s, with inactive control galaxies matched in stellar mass, rest-frame colour, size, Sersic index, and redshift. Using the GZH bar classifications of each sample, we demonstrate that AGN hosts show no statistically significant enhancement in bar fraction or average bar likelihood compared to closely-matched inactive galaxies. In detail, we find that the AGN bar fraction cannot be enhanced above the control bar fraction by more than a factor of two, at 99.7% confidence. We similarly find no significant difference in the AGN fraction among barred and non-barred galaxies. Thus we find no compelling evidence that large-scale bars directly fuel AGN at 0.2<z<1.0. This result, coupled with previous results at z=0, implies that moderate-luminosity AGN have not been preferentially fed by large-scale bars since z=1. Furthermore, given the low bar fractions at z>1, our findings suggest that large-scale bars have likely never directly been a dominant fueling mechanism for supermassive black hole growth.Comment: 13 pages, 5 figures, 2 tables, accepted by MNRA

Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress

A functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment

Black-wattle growth in reponse to application of nitrogen, phosphorus and potassium

Due to the lack of information about Black-wattle fertilization, this study evaluated black-wattle plants growth in response to different fertilization levels of nitrogen, phosphorus and potassium six years after implantation. The statistical design used was a randomized blocks with trifatorial distribution. Total height (m), diameter at breast height (DBH) (cm) and stem volume with bark (m³ ha-1) were evaluated. Black-wattle showed a positive and significant growth response to N and P (interaction) fertilizations and absence for K. m To obtain the maximum development of black-wattle, for the soil and climate condition studied, it is required the use of the maximum dose of nitrogen (40.0 kg ha-1 N) and 78.9 kg ha-1 phosphorus, not requiring the addition of potassium

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

A catalogue of faint local radio AGN and the properties of their host galaxies

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. ©: 2018 The Author(s). Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We present a catalogue of 2210 local ( z < 0.1) galaxies that contain faint active galactic nuclei (AGN). We select these objects by identifying galaxies that exhibit a significant excess in their radio luminosities, compared to what is expected from the observed levels of star formation activity in these systems. This is achieved by comparing the optical (spectroscopic) star formation rate (SFR) to the 1.4 GHz luminosity measured from the Faint Images of the Radio Sky at Twenty centimeters survey. The majority of the AGN identified in this study are fainter than those in previous work, such as in the Best and Heckman (2012) catalogue. We show that these faint AGN make a non-negligible contribution to the radio luminosity function at low luminosities (below 1022.5 W Hz−1), and host ∼13 per cent of the local radio luminosity budget. Their host galaxies are predominantly high stellar-mass systems (with a median stellar mass of 1011 M⊙), are found across a range of environments (but typically in denser environments than star-forming galaxies) and have early-type morphologies. This study demonstrates a general technique to identify AGN in galaxy populations where reliable optical SFRs can be extracted using spectro-photometry and where radio data are also available so that a radio excess can be measured. Our results also demonstrate that it is unsafe to infer SFRs from radio emission alone, even if bright AGN have been excluded from a sample, since there is a significant population of faint radio AGN that may contaminate the radio-derived SFRs.Peer reviewedFinal Published versio

Galaxy Zoo: Are bars responsible for the feeding of active galactic nuclei at 0.2<z<1.0?

We present a new study investigating whether active galactic nuclei (AGN) beyond the local universe are preferentially fed via large-scale bars. Our investigation combines data from Chandra and Galaxy Zoo: Hubble (GZH) in the AEGIS (All-wavelength Extended Groth strip International Survey), COSMOS (Cosmological Evolution Survey), and (Great Observatories Origins Deep Survey-South) GOODS-S surveys to create samples of face-on, disc galaxies at 0.21, our findings suggest that large-scale bars have likely never directly been a dominant fuelling mechanism for supermassive black hole growt