Explore the vast range of titles available.

The role of glutaminolysis in providing metabolites to support tumour growth is well-established, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated. Here we show that normal mammary epithelial cells consume glutamine, but do not secrete glutamate. Indeed, low levels of extracellular glutamate are necessary to maintain epithelial homoeostasis, and provision of glutamate drives disruption of epithelial morphology and promotes key characteristics of the invasive phenotype such as lumen-filling and basement membrane disruption. By contrast, primary cultures of invasive breast cancer cells convert glutamine to glutamate which is released from the cell through the system Xc- antiporter to activate a metabotropic glutamate receptor. This contributes to the intrinsic aggressiveness of these cells by upregulating Rab27-dependent recycling of the transmembrane matrix metalloprotease, MT1-MMP to promote invasive behaviour leading to basement membrane disruption. These data indicate that acquisition of the ability to release glutamate is a key watershed in disease aggressiveness. Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.

When an invading cancer cell attempts to pass through a hole in the extracellular matrix (ECM) which is too small for its nucleus, this generates physical tension. This tension is sensed by a nucleus–centrosome connection that activates trafficking of endosomal vesicles containing the matrix metalloprotease, MT1-MMP1 to the site of constraint. Recent evidence shows how focussed ECM degradation relieves the constraint and allows cancer cells to continue invading.

Mutant p53s (mutp53) increase cancer invasiveness by upregulating Rab-coupling protein (RCP) and diacylglycerol kinase-α (DGKα)-dependent endosomal recycling. Here we report that mutp53-expressing tumour cells produce exosomes that mediate intercellular transfer of mutp53’s invasive/migratory gain-of-function by increasing RCP-dependent integrin recycling in other tumour cells. This process depends on mutp53’s ability to control production of the sialomucin, podocalyxin, and activity of the Rab35 GTPase which interacts with podocalyxin to influence its sorting to exosomes. Exosomes from mutp53-expressing tumour cells also influence integrin trafficking in normal fibroblasts to promote deposition of a highly pro-invasive extracellular matrix (ECM), and quantitative second harmonic generation microscopy indicates that this ECM displays a characteristic orthogonal morphology. The lung ECM of mice possessing mutp53-driven pancreatic adenocarcinomas also displays increased orthogonal characteristics which precedes metastasis, indicating that mutp53 can influence the microenvironment in distant organs in a way that can support invasive growth. Some p53 mutants promote invasive migration of cancer cells and metastasis of tumours in vivo. However the key mechanistic details behind these phenomena remain unclear. Here the authors propose a non-cell autonomous mechanism involving fibroblasts, whereby mutant p53-expressing cancer cells activate an exosome-mediated mechanism that influences integrin recycling in fibroblasts, thus influencing extracellular matrix remodelling to favour cancer cell invasion and migration.

Formate overflow coupled to mitochondrial oxidative metabolism\\ has been observed in cancer cell lines, but whether that takes place in the tumor microenvironment is not known. Here we report the observation of serine catabolism to formate in normal murine tissues, with a relative rate correlating with serine levels and the tissue oxidative state. Yet, serine catabolism to formate is increased in the transformed tissue of in vivo models of intestinal adenomas and mammary carcinomas. The increased serine catabolism to formate is associated with increased serum formate levels. Finally, we show that inhibition of formate production by genetic interference reduces cancer cell invasion and this phenotype can be rescued by exogenous formate. We conclude that increased formate overflow is a hallmark of oxidative cancers and that high formate levels promote invasion via a yet unknown mechanism. Serine catabolism to formate supplies one-carbon units for biosynthesis. Here the authors show that formate production in murine cancers with high oxidative metabolism exceeds the biosynthetic demand and that high formate levels promotes invasion of cancer cells.

Colorectal cancer (CRC) is the second cause of cancer-related death; the CpG-island methylation pathway (CIMP) is associated with KRAS/BRAF mutations, two oncogenes rewiring cell metabolism, worse prognosis, and resistance to classical chemotherapies. Despite this, the question of a possible metabolic rewiring in CIMPs has never been investigated. Here, we analyse whether metabolic dysregulations are associated with tumour methylation by evaluating the transcriptome of CRC tumours. CIMP-high patients were found to present a hypermetabolism, activating mainly carbohydrates, folates, sphingolipids, and arachidonic acid metabolic pathways. A third of these genes had epigenetic targets of Myc in their proximal promoter, activating carboxylic acid, tetrahydrofolate interconversion, nucleobase, and oxoacid metabolisms. In the Myc signature, the expression of GAPDH, TYMS, DHFR, and TK1 was enough to predict methylation levels, microsatellite instability (MSI), and mutations in the mismatch repair (MMR) machinery, which are strong indicators of responsiveness to immunotherapies. Finally, we discovered that CIMP tumours harboured an increase in genes involved in the one-carbon metabolism, a pathway critical to providing nucleotides for cancer growth and methyl donors for DNA methylation, which is associated with worse prognosis and tumour hypermethylation. Transcriptomics could hence become a tool to help clinicians stratify their patients better.

The Rab GTPase effector, Rab-coupling protein (RCP) is known to promote invasive behaviour in vitro by controlling integrin and receptor tyrosine kinase (RTK) trafficking, but how RCP influences metastasis in vivo is unclear. Here we identify an RTK of the Eph family, EphA2, to be a cargo of an RCP-regulated endocytic pathway which controls cell:cell repulsion and metastasis in vivo . Phosphorylation of RCP at Ser 435 by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser 897 by Akt are both necessary to promote Rab14-dependent (and Rab11-independent) trafficking of EphA2 which generates cell:cell repulsion events that drive tumour cells apart. Genetic disruption of RCP or EphA2 opposes cell:cell repulsion and metastasis in an autochthonous mouse model of pancreatic adenocarcinoma—whereas conditional knockout of another RCP cargo, α5 integrin, does not suppress pancreatic cancer metastasis—indicating a role for RCP-dependent trafficking of an Eph receptor to drive tumour dissemination in vivo . Ephrin receptors mediate contact inhibition, but their intracellular trafficking during this process is unknown. Here the authors show that EphA2 receptor trafficking is regulated by the Rab GTPase effector Rab-coupling protein, which associates with Rab14-endosomes upon LMTK3-mediated phosphorylation.

Altered cellular metabolism has been associated with acquisition of invasive phenotypes during metastasis. To study this, we combined a genetically engineered mouse model of mammary carcinoma with syngeneic transplantation and primary tumour resection to generate isogenic cells from primary tumours and their corresponding lung micrometastases. Metabolic analyses indicated that micrometastatic cells increase proline production at the expense of glutathione synthesis leading to a reduction in total glutathione levels. Micrometastatic cells also have altered sphingomyelin metabolism leading to increased intracellular levels of specific ceramides. The combination of these two metabolic adaptations alters small extracellular vesicle (sEV) production to drive generation of an invasive microenvironment. Indeed, micrometastatic cells shut-down Rab27-dependent production of sEVs and, instead, switch-on neutral sphingomyelinase-2 (nSM2)-dependent sEV release. sEVs released in a nSM2-dependent manner from micrometastatic cells, in turn, influence the ability of fibroblasts to deposit extracellular matrix which promotes cancer cell invasiveness. These data provide evidence that metabolic rewiring drives invasive processes in metastasis by influencing sEV release. Breast cancer cells isolated from lung micrometastases have altered metabolism which influences extracellular vesicle production to generate invasive microenvironments.

Understanding the mechanisms that facilitate early events in metastatic seeding is key to developing therapeutic approaches to reduce metastasis – the leading cause of cancer-related death. Using whole animal screens in genetically engineered mouse models of cancer we have identified circulating metabolites associated with metastasis. Specifically, we highlight the pyrimidine uracil as a prominent metastasis-associated metabolite. Uracil is generated by neutrophils expressing the enzyme uridine phosphorylase-1 (UPP1), and neutrophil specific Upp1 expression is increased in cancer. Altered UPP1 activity influences expression of adhesion molecules on the surface of neutrophils, leading to decreased neutrophil motility in the pre-metastatic lung. Furthermore, we find that UPP1-expressing neutrophils suppress T-cell proliferation, and the UPP1 product uracil can increase fibronectin deposition in the extracellular microenvironment. Consistently, knockout or inhibition of UPP1 in mice with mammary tumours increases the number of T-cells and reduces fibronectin content in the lung and decreases the proportion of mice that develop lung metastasis. These data indicate that UPP1 influences neutrophil behaviour and extracellular matrix deposition in the lung and suggest that pharmacological targeting of this pathway could be an effective strategy to reduce metastasis.

Cell migration is essential to most living organisms. Single cell migration involves two distinct mechanisms, either a focal adhesion- and traction-dependent mesenchymal motility or an adhesion-independent but contractility-driven propulsive amoeboid locomotion. Cohesive migration of a group of cells, also called collective cell migration, has been only described as an adhesion- and traction-dependent mode of locomotion where the driving forces are mostly exerted at the front by leader cells. Here, by studying primary cancer specimens and cell lines from colorectal cancer, we demonstrate the existence of a second mode of collective migration which does not require adhesion to the surroundings and relies on a polarised supracellular contractility. Cell clusters confined into non-adhesive microchannels migrate in a rounded morphology, independently of the formation of focal adhesions or protruding leader cells, and lacking internal flow of cells, ruling-out classical traction-driven collective migration. Like single cells migrating in an amoeboid fashion, the clusters display a supracellular actin cortex with myosin II enriched at the rear. Using pharmacological inhibitors and optogenetics, we show that this polarised actomyosin activity powers migration and propels the clusters. This new mode of migration, that we named collective amoeboid, could be enabled by intrinsic or extrinsic neoplasic features to enable the metastatic spread of cancers. Competing Interest Statement The authors have declared no competing interest.

Introduction and history of cashew cultivation. The location of Côte d’Ivoire promotes the cultivation of cashew (Anacardium occidentale) in the northern half of the country. Indeed, introduced in 1960 to fight against erosion and halt the advancing desert, this crop has become a perennial source of income for more than 150,000 farmers gathered in twenty cooperatives and allows more than 1.5 M people to earn a living. The Ivorian cashew production increased from 6,000 t·year-1 in 1990 to 330,000 t·year-1 in 2008, with a forecast of 350,000 t·year-1 in 2009. Organization of the cashew sector. However, the sector is facing enormous problems including the disorganization of operators and the non-processing of cashews. The disorganization of the sector’s operators does not promote collaborative resolution of issues of common interest. This results in all sorts of speculation by intermediaries. The existing structures do not work synergistically, so that the price of cashew per kg paid to producers varies in the same country, from one region to the other, and even according to the buyers. Strategic and institutional environment. The problems of processing cashew nuts are due on the one hand to the investment code that does not favor the installation of medium-sized processing units (2,500 t·year-1) and, on the other hand, to private banks which require too many guarantees to fund investors. Conclusion. The cashew industry has a future in Côte d’Ivoire provided that the operators are organized, and that the Ivorian state establishes a regulatory and institutional framework to facilitate the installation of investors. Introduction et histoire de la culture de l’anacarde. La situation géographique de la Côte d’ivoire favorise la culture de l’anacarde (Anacardium occidentale) dans la moitié nord du pays. En effet, introduite dans les année 1960 pour lutter contre l’érosion et freiner l’avancée du désert, cette filière est devenue une culture pérenne génératrice de revenus pour plus de 150 000 producteurs regroupés dans une vingtaine de coopératives et faisant vivre plus de 1,5 M de personnes. La production ivoirienne est donc passée de 6 000 t·an-1 en 1990 à 350 000 t·an-1 en 2008 avec une prévision de 350 000 t·an-1 en 2009. Organisation du secteur de l’anacarde. Cependant cette filière est confrontée à d’énormes problèmes dont l’inorganisation des opérateurs et la non transformation des noix de cajou. L’inorganisation des opérateurs de cette filière ne favorise pas la résolution concertée des problèmes d’intérêts communs. Cela se traduit par toutes sortes de spéculation par les intermédiaires. Les structures existantes ne travaillent pas en synergie, si bien que le prix du kg d’anacardes payé aux producteurs varie au cours de la même campagne, d’une région à une autre et même en fonction des acheteurs. Stratégie et environnement institutionnel. Les problèmes de transformation des noix de cajou sont dus, quant à eux, d’une part au code d’investissement qui ne favorise pas l’installation d’unités de transformation moyennes (2 500 t·an-1) et, d’autre part, aux banques privées qui exigent trop de garanties pour financer les investisseurs. Conclusion. La filière de la noix de cajou a de l’avenir en Côte d’Ivoire pourvu que les opérateurs s’organisent et que l’Etat ivoirien mette en place un cadre réglementaire et institutionnel pour favoriser l’installation des investisseurs. Introducción e historia del cultivo del anarcado. La situación geográfica de Côte d’Ivoire favorece el cultivo del anacardo (Anacardium occidentale) en la mitad norte del país. En efecto, este sector de actividad, introducido en los años 1960 para luchar contra la erosión y frenar el avance del desierto, se volvió un cultivo perenne, generador de ingresos para más de 150 000 productores, agrupados en unas veinte cooperativas, que permiten vivir a más de 1,5 millones de personas. Por lo tanto, la producción pasó de 6 000 t·año-1 en 1990 a 330 000 t· año-1 en 2008, con una previsión de 350 000 t·año-1 en 2009. Organización del sector del anacardo. Sin embargo, este sector de actividad se ve enfrentado a enormes problemas, como, por ejemplo, la desorganización de los operadores y la no transformación de la nuez de anacardo. La desorganización de los operadores de este sector de actividad no favorece la resolución de común acuerdo de los problemas de interés común. Esto se traduce a todo tipo de especulación por parte de los intermediarios. Las estructuras existentes no trabajan conjuntamente, por lo que el precio del kilo de anacardo pagado a los productores varía dentro de un mismo campo, de una región a otra e, incluso, en función de los compradores. Estrategia y entorno institucional. Los problemas de transformación de las nueces de anacardo, por lo que a ellos se refiere, se deben, por un lado, al código de inversión que no favorece la instalación de unidades medias de transformación (2 00 t·año-1) y, por otro lado, a las bancas privadas, que exigen demasiadas garantías para financiar a los inversores. Conclusión. El sector de actividad de la nuez de anacardo tiene futuro en Côte d’Ivoire, siempre y cuando los operadores se organicen y que el Estado instaure un marco reglamentario e institucional para favorecer la instalación de los inversores.