Redefining the relationship between gene dosage and tumor suppression.
In this Perspective, autopsy results and literature are presented supporting the hypothesis that neutrophil extracellular traps (NETs) may contribute to organ damage and mortality in COVID-19. If correct, existing drugs that target NETs, although unspecific, may benefit COVID-19 patients.
This Perspective explores the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offers suggestions to both understand and therapeutically modulate anti-COVID immunity.
Brief Definitive Reports
This study unravels an unprecedented murine model of lethal metastatic prostate cancer, based on the combined deletion of Pten and Lkb1. Importantly, minimal activity of LKB1 is sufficient to hamper prostate cancer cell aggressiveness, thus redefining the relationship between gene dosage and tumor suppression.
Badhai et al. describe a mouse model of mesothelioma with combined deletion of Bap1, Nf2, and Cdkn2ab that shows rapid onset and recapitulates human mesothelioma including its response to the standard treatment. This autochthonous model is well suited for testing cancer immunotherapies.
Ramalingam et al. demonstrate that pharmacological inhibition of mTOR adversely impacts aging hematopoiesis. The authors demonstrate that aging results in decreased mTOR signaling within the bone marrow endothelium and endothelial-specific inhibition of mTOR causes hematopoietic defects observed during physiological aging.
Whyte et al. demonstrate that regulation of intratumor CCL21 and DC trafficking from tumors by the atypical chemokine receptor 4 curtails intratumor CD8+ T cell accumulation and immunotherapy efficacy.
Technical Advances and Resources
Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes
By single-cell RNA sequencing, Zakharov et al. examine the cellular contents of pancreatic islets at three developmental stages in autoimmune diabetes. From diabetes inception, islets show marked cellular heterogeneity, which progresses with time and includes T cells, macrophages, and dendritic cells.
Dominant-negative variants of STAT3 do not account for all cases of autosomal dominant hyper-IgE syndrome (HIES). Béziat et al. report HIES patients with dominant-negative variations of IL6ST, encoding the GP130 receptor, which normally recruits STAT3 upon stimulation with IL-6 and related cytokines.
Hippo/Mst signaling coordinates cellular quiescence with terminal maturation in iNKT cell development and fate decisions
The Hippo kinase Mst1 enforces the establishment of cellular quiescence for terminal maturation and reciprocal fate decisions between iNKT1 and iNKT17 effector cells, which respectively depend upon Opa1-mediated mitochondrial dynamics and ICOS–mTORC2 signaling.
Using an in vivo real-time approach, the authors show that local myeloid cells remove early CNS-invading T cells via an engulfment pathway that is dependent on N-acetyl-D-glucosamine (GlcNAc) and lectin. These results reveal a novel capacity of myeloid cells to counteract neuroinflammation.
The authors report the transcriptome of mouse retinal pigment epithelium/choroid tissue at single-cell resolution. A subset of choroidal endothelial cells expresses Indian Hedgehog, which targets mesenchymal stem cell–like cells regulating mast cell survival and the inflammatory response after damage.
Hepatic stellate cell–specific knockout of transcriptional intermediary factor 1γ aggravates liver fibrosis
This study demonstrates that loss of TIF1γ in HSC aggravates fibrosis and that TIF1γ, identified as a novel target, has potential in the development of new therapeutic approaches to inhibiting or treating liver fibrosis.
Morcos et al. show that there is no evidence for abrupt entry of aging hematopoietic stem cells into quiescence after four divisions as previously suggested. They examine factors confounding pulse-chase experiments in H2B-fusion protein transgenic mice that can lead to misinterpretations of HSC proliferative behavior.
Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function
Human lung tumors engage in substantial mitochondrial metabolism. Here, Ward et al. demonstrate that nicotinamide nucleotide transhydrogenase (NNT) supports oxidative metabolism in NSCLC by mitigating Fe-S cluster oxidation.
The transcription factor PRDM16 is epigenetically silenced in kidney cancer. Loss of this factor’s repressive properties promotes HIF-mediated induction of the protumorigenic factor SEMA5B. These data provide a novel epigenetic mechanism by which HIF signaling is promoted in this malignancy.
An et al. identify a novel MST4-mediated YAP inactivation signaling pathway and demonstrate that the MST4–YAP axis is required to suppress gastric tumorigenesis in vivo.