LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc- . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

Ferroptosis: Concepts and Definitions.

Ferroptosis is a newly discovered form of cell death that is rapidly becoming associated to a variety of diseases and explaining their pathological mechanisms. This book addresses new emerging topics in the field of ferroptosis, with special attention to diseases more recently explained through ferroptotic mechanisms, including infectious diseases and neurodegeneration. In this chapter, we will provide the readers with an introduction to the concepts and pathways involved in ferroptosis to further move into a more detailed exposition of the topics advertised in this book. In special, we aim for this book to broaden the perspectives on how ferroptosis is regulated and connected to human diseases and motivate new studies in this emerging field.

Cell-Cycle Position of Single MYC-Driven Cancer Cells Dictates Their Susceptibility to a Chemotherapeutic Drug.

While many tumors initially respond to chemotherapy, regrowth of surviving cells compromises treatment efficacy in the long term. The cell-biological basis of this regrowth is not understood. Here, we characterize the response of individual, patient-derived neuroblastoma cells driven by the prominent oncogene MYC to the first-line chemotherapy, doxorubicin. Combining live-cell imaging, cell-cycle-resolved transcriptomics, and mathematical modeling, we demonstrate that a cell's treatment response is dictated by its expression level of MYC and its cell-cycle position prior to treatment. All low-MYC cells enter therapy-induced senescence. High-MYC cells, by contrast, disable their cell-cycle checkpoints, forcing renewed proliferation despite treatment-induced DNA damage. After treatment, the viability of high-MYC cells depends on their cell-cycle position during treatment: newborn cells promptly halt in G1 phase, repair DNA damage, and form re-growing clones; all other cells show protracted DNA repair and ultimately die. These findings demonstrate that fast-proliferating tumor cells may resist cytotoxic treatment non-genetically, by arresting within a favorable window of the cell cycle.

Exploring epistasis in candidate genes for antisocial personality disorder.

OBJECTIVE: To identify and characterize high-order gene-to-gene interactions in antisocial personality disorder (ASPD). METHODS: Participants for case-control study were selected from the inmate male population in Bellavista prison from Medellin. The study included 310 individuals with ASPD and 200 with no ASPD. Diagnoses were made according to a best-estimate procedure based on a semistructured interview (diagnostic interview for genetic studies 3.0). We genotyped some single-nucleotide polymorphisms in candidate genes with main serotonin pathway effects. The gene-gene interaction was examined using the multifactor dimensionality reduction method version 2.0.α. We assessed model sizes of 2 and 3 loci and counted the number of replicates that contained the causal loci in the final best model that was identified using 10-fold cross validation. RESULTS: We find epistatic interaction with catechol-O-methyl transferase (COMT), tryptophan hydroxylase, and 5-HTR2A (serotonin receptor) with ASPD. This data supports an important role of polymorphism in serotonin receptors and low enzyme activity of COMT for susceptibility to ASPD. CONCLUSION: This study suggests that gene interactions between genetic variants in COMT, 5-HTR2A and tryptophan hydroxylase gene would be associated with ASPD and influence the dopamine rewards pathways and modulate serotonin levels in ASPD.

Protein network prediction and topological analysis in Leishmania major as a tool for drug target selection.

BACKGROUND: Leishmaniasis is a virulent parasitic infection that causes a worldwide disease burden. Most treatments have toxic side-effects and efficacy has decreased due to the emergence of resistant strains. The outlook is worsened by the absence of promising drug targets for this disease. We have taken a computational approach to the detection of new drug targets, which may become an effective strategy for the discovery of new drugs for this tropical disease. RESULTS: We have predicted the protein interaction network of Leishmania major by using three validated methods: PSIMAP, PEIMAP, and iPfam. Combining the results from these methods, we calculated a high confidence network (confidence score > 0.70) with 1,366 nodes and 33,861 interactions. We were able to predict the biological process for 263 interacting proteins by doing enrichment analysis of the clusters detected. Analyzing the topology of the network with metrics such as connectivity and betweenness centrality, we detected 142 potential drug targets after homology filtering with the human proteome. Further experiments can be done to validate these targets. CONCLUSION: We have constructed the first protein interaction network of the Leishmania major parasite by using a computational approach. The topological analysis of the protein network enabled us to identify a set of candidate proteins that may be both (1) essential for parasite survival and (2) without human orthologs. These potential targets are promising for further experimental validation. This strategy, if validated, may augment established drug discovery methodologies, for this and possibly other tropical diseases, with a relatively low additional investment of time and resources.