The glucose transporter 2 regulates CD8 T cell function via environment sensing.

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8 T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage.

Centrosome amplification fine tunes tubulin acetylation to differentially control intracellular organization.

Intracellular organelle organization is conserved in eukaryotic cells and is primarily achieved through active transport by motor proteins along the microtubule cytoskeleton. Microtubule post-translational modifications (PTMs) can contribute to microtubule diversity and differentially regulate motor-mediated transport. Here, we show that centrosome amplification, commonly observed in cancer and shown to promote aneuploidy and invasion, induces a global change in organelle positioning towards the cell periphery and facilitates nuclear migration through confined spaces.

Low HER2 expression in normal breast epithelium enables dedifferentiation and malignant transformation via chromatin opening.

Overexpression of the HER2 protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. We used an inducible breast cancer transformation system that allows investigation of early molecular changes. HER2 overexpression to similar levels as those observed in a subtype of HER2-positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered the transcriptional programme of genes associated with oncogenic transformation.

Too close for comfort? Endomembranes promote missegregation by enclosing lost chromosomes.

Correct segregation of chromosomes during mitosis is essential to prevent aneuploidy. In this issue, Ferrandiz et al. (2022.

Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption.

Bidirectional communication between cells and their surrounding environment is critical in both normal and pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules between cells, are recognized as an important constituent of cell-cell communication. In cancer, alterations in EV secretion contribute to the growth and metastasis of tumor cells.

Oxidative Stress in Cells with Extra Centrosomes Drives Non-Cell-Autonomous Invasion.

Centrosomal abnormalities, in particular centrosome amplification, are recurrent features of human tumors. Enforced centrosome amplification in vivo plays a role in tumor initiation and progression. However, centrosome amplification occurs only in a subset of cancer cells, and thus, partly due to this heterogeneity, the contribution of centrosome amplification to tumors is unknown.

Structural Centrosomal Abnormalities Push Cells toward Invasion.

Structural centrosomal aberrations have long been described in cancer, but their impact on cell physiology and tumorigenesis remains unclear. Ganier et al. (2018) show that centrosome structural abnormalities facilitate cell dissemination by promoting budding of epithelial mitotic cells.

Over-elongation of centrioles in cancer promotes centriole amplification and chromosome missegregation.

Centrosomes are the major microtubule organising centres of animal cells. Deregulation in their number occurs in cancer and was shown to trigger tumorigenesis in mice. However, the incidence, consequence and origins of this abnormality are poorly understood.

Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells.

Centrosome amplification is a common feature of human tumors. To survive, cancer cells cluster extra centrosomes during mitosis, avoiding the detrimental effects of multipolar divisions. However, it is unclear whether clustering requires adaptation or is inherent to all cells.

Dividing with Extra Centrosomes: A Double Edged Sword for Cancer Cells.

The presence of supernumerary centrosomes is a hallmark of human tumours. Recent work in animal models suggests that extra centrosomes are not just bystanders in cancer but can accelerate tumourigenesis in the absence of the tumour suppressor p53. Centrosome amplification could indeed actively participate in tumour progression through the induction of chromosome instability, disruption of tissue architecture and promoting cell invasion.

Centrosomes: PIDDosome Joins the Counting Game.

Centrosome numbers are tightly regulated during the cell cycle. A new study shows that the PIDDosome prevents the propagation of cells carrying amplified centrosomes via p53 stabilisation and p21-mediated cell-cycle arrest, thus ensuring the maintenance of normal centrosome numbers.

Studying centrosome function using three-dimensional cell cultures.

Three-dimensional (3D) cell cultures have long been recognized as a tool for the study of tissue architecture, polarity, and invasion. However, only recently these systems have been used to study centrosome and cilia functions. Studying these organelles in 3D cultures has elucidated new functions that otherwise would have been overlooked, demonstrating the value of these experimental systems to the field.

Concerted copy number variation balances ribosomal DNA dosage in human and mouse genomes.

Tandemly repeated ribosomal DNA (rDNA) arrays are among the most evolutionary dynamic loci of eukaryotic genomes. The loci code for essential cellular components, yet exhibit extensive copy number (CN) variation within and between species. CN might be partly determined by the requirement of dosage balance between the 5S and 45S rDNA arrays.

Centrosome amplification and cancer: Branching out.

Despite being a common feature of human cancer, the role of supernumerary centrosomes in tumourigenesis is still poorly understood. We have recently described a novel role for centrosome amplification in promoting cell invasion that could impact tumor progression.

Oncogene-like induction of cellular invasion from centrosome amplification.

Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumour progression.

The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers.

Germinal centers (GCs) are sites of intense B cell proliferation and are central for T cell-dependent antibody responses. However, the role of c-Myc, a key cell-cycle regulator, in this process has been questioned. Here we identified c-Myc(+) B cell subpopulations in immature and mature GCs and found, by genetic ablation of Myc, that they had indispensable roles in the formation and maintenance of GCs.

Centrosomes and cilia in human disease.

Centrioles are microtubule-derived structures that are essential for the formation of centrosomes, cilia and flagella. The centrosome is the major microtubule organiser in animal cells, participating in a variety of processes, from cell polarisation to cell division, whereas cilia and flagella contribute to several mechanisms in eukaryotic cells, from motility to sensing. Although it was suggested more than a century ago that these microtubule-derived structures are involved in human disease, the molecular bases of this association have only recently been discovered.

Cytokinesis failure occurs in Fanconi anemia pathway-deficient murine and human bone marrow hematopoietic cells.

Fanconi anemia (FA) is a genomic instability disorder characterized by bone marrow failure and cancer predisposition. FA is caused by mutations in any one of several genes that encode proteins cooperating in a repair pathway and is required for cellular resistance to DNA crosslinking agents. Recent studies suggest that the FA pathway may also play a role in mitosis, since FANCD2 and FANCI, the 2 key FA proteins, are localized to the extremities of ultrafine DNA bridges (UFBs), which link sister chromatids during cell division.

A mechanism linking extra centrosomes to chromosomal instability.

Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells.

Centrosomes and cancer: how cancer cells divide with too many centrosomes.

Precise control of centrosome number is crucial for bipolar spindle assembly and accurate transmission of genetic material to daughter cells. Failure to properly control centrosome number results in supernumerary centrosomes, which are frequently found in cancer cells. This presents a paradox: during mitosis, cells with more than two centrosomes are prone to multipolar mitoses and cell death, however, cancer cells possessing extra centrosomes usually divide successfully.

A role for Drosophila Polo protein in chromosome resolution and segregation during mitosis.

Correct chromosome structure is essential to ensure faithful segregation during mitosis. Chromosome condensation occurs at the same time as cohesion is released from the arms of the sister chromatids. It is not until metaphase-anaphase transition that chromosomes lose cohesion completely, by proteolysis of the component of the cohesin complex Scc1 (Sister chromatid cohesion 1).

Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes.

Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer cells defined mechanisms that suppress multipolar mitoses.

Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors.

The forkhead transcription factor FoxM1 has been reported to regulate, variously, proliferation and/or spindle formation during the G2/M transition of the cell cycle. Here we define specific functions of FoxM1 during brain development by the investigation of FoxM1 loss-of-function mutations in the context of Sonic hedgehog (Shh)-induced neuroproliferation in cerebellar granule neuron precursors (CGNP). We show that FoxM1 is expressed in the cerebellar anlagen as well as in postnatal proliferating CGNP and that it is upregulated in response to activated Shh signaling.