Zeb2 drives invasive and microbiota-dependent colon carcinoma.

Colorectal cancer (CRC) is highly prevalent in Western society, and increasing evidence indicates strong contributions of environmental factors and the intestinal microbiota to CRC initiation, progression and even metastasis. We have identified a synergistic inflammatory tumor-promoting mechanism through which the resident intestinal microbiota boosts invasive CRC development in an epithelial-to-mesenchymal transition-prone tissue environment. Intestinal epithelial cell (IEC)-specific transgenic expression of the epithelial-to-mesenchymal transition regulator Zeb2 in mice (Zeb2) leads to increased intestinal permeability, myeloid cell-driven inflammation and spontaneous invasive CRC development.

2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer.

Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism.

Cracking the Monoubiquitin Code of Genetic Diseases.

Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent studies uncovered the role of single ubiquitin modification in important physiological processes. Monoubiquitination can modulate the stability, subcellular localization, binding properties, and activity of the target proteins.

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.

The Noonan Syndrome Gene Controls Cardiovascular Function by Regulating Vesicular Trafficking.

Rationale: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches.

Gemcitabine Recruits M2-Type Tumor-Associated Macrophages into the Stroma of Pancreatic Cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease that can develop therapy resistance over time. The dense stroma in PDAC plays a critical role in tumor progression and resistance. How this stroma interacts with the tumor cells and how this is influenced by chemotherapy remain poorly understood.

CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.

Depleting regulatory T cells (T cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T cells as a central metabolic modulator.

Dynamic ROS Regulation by TIGAR: Balancing Anti-cancer and Pro-metastasis Effects.

The role of ROS in cancer is complex, with studies demonstrating both pro- and anti-tumor effects. In a pancreatic ductal adenocarcinoma model, ROS limitation through TIGAR has been shown to initially support cancer development but to later become a metabolic liability in metastasizing cells that is counteracted by decreased TIGAR expression.

ATP13A2 deficiency disrupts lysosomal polyamine export.

ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome-a parkinsonism with dementia-and early-onset Parkinson's disease. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson's disease, whereas loss of ATP13A2 compromises lysosomes. However, the transport function of ATP13A2 in lysosomes remains unclear.

Co-regulation of the antagonistic RepoMan:Aurora-B pair in proliferating cells.

Chromosome segregation during mitosis is antagonistically regulated by the Aurora-B kinase and RepoMan (recruits PP1 onto mitotic chromatin at anaphase)-associated phosphatases PP1/PP2A. Aurora B is overexpressed in many cancers but, surprisingly, this only rarely causes lethal aneuploidy. Here we show that RepoMan abundance is regulated by the same mechanisms that control Aurora B, including FOXM1-regulated expression and proteasomal degradation following ubiquitination by APC/C-CDH1 or SCF.

Stress-induced lncRNA LASTR fosters cancer cell fitness by regulating the activity of the U4/U6 recycling factor SART3.

Dysregulated splicing is a common event in cancer even in the absence of mutations in the core splicing machinery. The aberrant long non-coding transcriptome constitutes an uncharacterized level of regulation of post-transcriptional events in cancer. Here, we found that the stress-induced long non-coding RNA (lncRNA), LINC02657 or LASTR (lncRNA associated with SART3 regulation of splicing), is upregulated in hypoxic breast cancer and is essential for the growth of LASTR-positive triple-negative breast tumors.

Stable Isotopes for Tracing Mammalian-Cell Metabolism In Vivo.

Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation.

Analyzing the Metabolism of Metastases in Mice.

Metastasis formation is the leading cause of death in cancer patients. It has recently emerged that cancer cells adapt their metabolism to successfully transition through the metastatic cascade. Consequently, measuring and analyzing the in vivo metabolism of metastases has the potential to reveal novel treatment strategies to prevent metastasis formation.

The sixth international RASopathies symposium: Precision medicine-From promise to practice.

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches.

Mutations in Cause Metabolic Reprogramming and Disruption of the Electron Transfer.

Complex I (CI) is the first enzyme of the mitochondrial respiratory chain and couples the electron transfer with proton pumping. Mutations in genes encoding CI subunits can frequently cause inborn metabolic errors. We applied proteome and metabolome profiling of patient-derived cells harboring pathogenic mutations in two distinct CI genes to elucidate underlying pathomechanisms on the molecular level.

Differentiation but not ALS mutations in FUS rewires motor neuron metabolism.

Energy metabolism has been repeatedly linked to amyotrophic lateral sclerosis (ALS). Yet, motor neuron (MN) metabolism remains poorly studied and it is unknown if ALS MNs differ metabolically from healthy MNs. To address this question, we first performed a metabolic characterization of induced pluripotent stem cells (iPSCs) versus iPSC-derived MNs and subsequently compared MNs from ALS patients carrying FUS mutations to their CRISPR/Cas9-corrected counterparts.

Hallmarks of Endothelial Cell Metabolism in Health and Disease.

In 2009, it was postulated that endothelial cells (ECs) would only be able to execute the orders of growth factors if these cells would accordingly adapt their metabolism. Ten years later, it has become clear that ECs, often differently from other cell types, rely on distinct metabolic pathways to survive and form new blood vessels; that manipulation of EC metabolic pathways alone (even without changing angiogenic signaling) suffices to alter vessel sprouting; and that perturbations of these metabolic pathways can underlie excess formation of new blood vessels (angiogenesis) in cancer and ocular diseases. Initial proof of evidence has been provided that targeting (normalizing) these metabolic perturbations in diseased ECs and delivery of metabolites deserve increasing attention as novel therapeutic approaches for inhibiting or stimulating vessel growth in multiple disorders.

Functional reprogramming of regulatory T cells in the absence of Foxp3.

Regulatory T cells (T cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (T) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient T cells ameliorated disease in a Foxo1 transcription factor-dependent manner.

Metabolic vulnerabilities of metastasizing cancer cells.

Most cancer patients die due to metastasis formation. Therefore, understanding, preventing, and treating metastatic cancers is an unmet need. Recent research indicates that cancer cells that undergo metastasis formation have a distinct metabolism that can be targeted.

Radiosensitization approaches for HPV-positive and HPV-negative head and neck squamous carcinomas.

Radiotherapy is one of the most used treatment approaches for head and neck squamous cell carcinoma (HNSCC). Targeted inhibition of DNA repair machinery has the potential to improve treatment response by tailoring treatment to cancer cells lacking specific DNA repair pathways. Human papillomavirus (HPV)-negative and HPV-positive HNSCCs respond differently to radiotherapy treatment, suggesting that different approaches of DNA repair inhibition should be employed for these HNSCC groups.

Peptide-guided nanoparticles for glioblastoma targeting.

Tumor-selective drug conjugates can potentially improve the prognosis for patients affected by glioblastoma (GBM) - the most common and malignant type of brain cancer with no effective cure. Here we evaluated a novel tumor penetrating peptide that targets cell surface p32, LinTT1 (AKRGARSTA), as a GBM targeting ligand for systemically-administered nanoparticles. LinTT1-functionalization increased tumor homing of iron oxide nanoworms (NWs) across a panel of five GBM models ranging from infiltratively-disseminating to angiogenic phenotypes.

Publisher Correction: Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells.

Somatic ribosomal protein mutations have recently been described in cancer, yet their impact on cellular transcription and translation remains poorly understood. Here, we integrate mRNA sequencing, ribosome footprinting, polysomal RNA sequencing and mass spectrometry datasets from a mouse lymphoid cell model to characterize the T-cell acute lymphoblastic leukemia (T-ALL) associated ribosomal RPL10 R98S mutation. Surprisingly, RPL10 R98S induces changes in protein levels primarily through transcriptional rather than translation efficiency changes.

GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients.

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for the generation of lipid nutrients for adjacent parenchymal cells.