Hypermethylated Colorectal Cancer Tumours Present a Myc-Driven Hypermetabolism with a One-Carbon Signature Associated with Worsen Prognosis.

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.

Cell clusters adopt a collective amoeboid mode of migration in confined nonadhesive environments.

Cell migration is essential to living organisms and deregulated in cancer. Single cell's migration ranges from traction-dependent mesenchymal motility to contractility-driven propulsive amoeboid locomotion, but collective cell migration has only been described as a focal adhesion-dependent and traction-dependent process. Here, we show that cancer cell clusters, from patients and cell lines, migrate without focal adhesions when confined into nonadhesive microfabricated channels.

Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels.

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.

Cancer cells with trapped nuclei cut their way through the extracellular matrix.

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.

Increased formate overflow is a hallmark of oxidative cancer.

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.

Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells.

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.

Regulation of the trafficking and the function of the metalloprotease ADAM10 by tetraspanins.

By interacting directly with partner proteins and with one another, tetraspanins organize a network of interactions referred to as the tetraspanin web. ADAM10 (A Disintegrin And Metalloprotease 10), an essential membrane-anchored metalloprotease that cleaves off the ectodomain of a large variety of cell surface proteins including cytokines, adhesion molecules, the precursor of the β-amyloid peptide APP or Notch, has emerged as a major component of the tetraspanin web. Recent studies have shown that ADAM10 associates directly with all members (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33) of a subgroup of tetraspanins having eight cysteines in the large extracellular domain and referred to as TspanC8.

New insights into the tetraspanin Tspan5 using novel monoclonal antibodies.

Tspan5 is a member of a subgroup of tetraspanins referred to as TspanC8. These tetraspanins directly interact with the metalloprotease ADAM10, regulate its exit from the endoplasmic reticulum and subsequent trafficking, and differentially regulate its ability to cleave various substrates and activate Notch signaling. The study of Tspan5 has been limited by the lack of good antibodies.

Tensin links energy metabolism to extracellular matrix assembly.

The regulation of integrin function is key to fundamental cellular processes, including cell migration and extracellular matrix (ECM) assembly. In this issue, Georgiadou et al. (2017.

Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion.

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 by Lemur tyrosine kinase-3 (LMTK3) and of EphA2 at Ser 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.

A proteomic approach to identify endosomal cargoes controlling cancer invasiveness.

We have previously shown that Rab17, a small GTPase associated with epithelial polarity, is specifically suppressed by ERK2 (also known as MAPK1) signalling to promote an invasive phenotype. However, the mechanisms through which Rab17 loss permits invasiveness, and the endosomal cargoes that are responsible for mediating this, are unknown. Using quantitative mass spectrometry-based proteomics, we have found that knockdown of Rab17 leads to a highly selective reduction in the cellular levels of a v-SNARE (Vamp8).

TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals.

The metalloprotease ADAM10/Kuzbanian catalyzes the ligand-dependent ectodomain shedding of Notch receptors and activates Notch. Here, we show that the human tetraspanins of the evolutionary conserved TspanC8 subfamily (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33) directly interact with ADAM10, regulate its exit from the endoplasmic reticulum, and that four of them regulate ADAM10 surface expression levels. In an independent RNAi screen in Drosophila, two TspanC8 genes were identified as Notch regulators.