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Plasma renin activity (PRA) and plasma concentrations of angiotensin II (AngII), atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) were determined in the abdominal aorta and the renal veins before and 1 h after peroral ingestion of captopril 25 mg in 29 patients with arterial hypertension and unilateral renal artery stenosis or occlusion, in order to study the effect of ACE inhibition on single-kidney extraction ratio (ER) of PRA, AngII, ANP, and AVP, and on renal vein renin ratio (RVRR). PRA was increased, AngII and ANP were reduced, and AVP unchanged after captopril. On the affected side the negative ER of PRA (−1.03) and AngII (−0.28) and the positive ER of ANP (0.25) and AVP (0.14) were not significantly changed by captopril. On the non-affected side ER of AngII and ER of ANP were significantly reduced (ER of AngII, 0.41–0.00, ER of ANP, 0.29–0.17), but ER of PRA and ER of AVP were unchanged. RVRR was not significantly changed by captopril. RVRR was greater than 1.5 in 79% of the patients before captopril, in 82% after captopril, and in 93% either before or after captopril. It is concluded that captopril reduces ER of AngII and ER of ANP on the non-affected side but not on the affected side in unilateral renal artery disease with hypertension, and that the use of RVRR both before and after captopril improves the predictive value of RVRR with regard to the diagnosis of unilateral renal artery disease. [ABSTRACT FROM PUBLISHER]

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of MTM1 -the phosphatase antagonist of VPS34-we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.

A new study by Folkert et al. (https://doi.org/10.1084/jem.20230420) defines an "iron-rich" subset of tumor-associated macrophages (iTAMs). The metabolism of heme leads to the degradation of the transcriptional repressor Bach1 and shapes the transcriptional profile of iTAMs. The endothelin receptor B in iTAMs signals tumor-supportive functions., (© 2024 Sun and Egeblad.)

Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B + natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B + NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are poorly understood. Here we performed marker-based genetic screens in search of factors needed to maintain basal identity in pancreatic ductal adenocarcinoma (PDAC). This approach revealed MED12 as a powerful regulator of the basal cell state in this disease. Using biochemical reconstitution and epigenomics, we show that MED12 carries out this function by bridging the transcription factor ΔNp63, a known master regulator of the basal lineage, with the Mediator complex to activate lineage-specific enhancer elements. Consistent with this finding, the growth of basal-like PDAC is hypersensitive to MED12 loss when compared to PDAC cells lacking basal characteristics. Taken together, our genetic screens have revealed a biochemical interaction that sustains basal identity in human cancer, which could serve as a target for tumor lineage-directed therapeutics., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Exposure to pathogens throughout a lifetime influences immunity and organ function. Here, we explore how the systemic host-response to bacterial urinary tract infection (UTI) induces tissue-specific alterations to the mammary gland. Utilizing a combination of histological tissue analysis, single cell transcriptomics, and flow cytometry, we identify that mammary tissue from UTI-bearing mice displays collagen deposition, enlarged ductal structures, ductal hyperplasia with atypical epithelial transcriptomes and altered immune composition. Bacterial cells are absent in the mammary tissue and blood of UTI-bearing mice, therefore, alterations to the distal mammary tissue are mediated by the systemic host response to local infection. Furthermore, broad spectrum antibiotic treatment resolves the infection and restores mammary cellular and tissue homeostasis. Systemically, unresolved UTI correlates with increased plasma levels of the metalloproteinase inhibitor, TIMP1, which controls extracellular matrix remodeling and neutrophil function. Treatment of nulliparous and post-lactation UTI-bearing female mice with a TIMP1 neutralizing antibody, restores mammary tissue normal homeostasis, thus providing evidence for a link between the systemic host response during UTI and mammary gland alterations., (© 2024. The Author(s).)

Summary: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system., (©2024 American Association for Cancer Research.)

Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress significantly alters the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis. Chronic stress shifts normal circadian rhythm of neutrophils and causes increased neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Furthermore, digesting NETs with DNase I prevents chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease., Competing Interests: Declaration of interests M.E. serves on the advisory board of Cancer Cell. C.R.V. has received consulting fees from Flare Therapeutics, Roivant Sciences, and C4 Therapeutics; has served on the advisory boards of KSQ Therapeutics, Syros Pharmaceuticals, and Treeline Biosciences; and owns stock from Treeline Biosciences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cancer alters the function of multiple organs beyond those targeted by metastasis 1,2 . Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1β, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-αvβ1, which traps latent TGF-β, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-β. TGF-β activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1β-NET-TGF-β axis., Competing Interests: Declaration of interests M.E. is a member of the research advisory board for brensocatib for Insmed, Inc., a member of the scientific advisory board for Vividion Therapeutics, Inc., and a consultant for Protalix, Inc., and holds shares in Agios Pharmaceuticals, Inc. J.A., C.G., and A.M. have a patent related to this work (EP22306004)., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cancer immunotherapies, including adoptive T cell transfer, can be ineffective because tumors evolve to display antigen-loss-variant clones. Therapies that activate multiple branches of the immune system may eliminate escape variants. Here, we show that melanoma-specific CD4 + T cell therapy in combination with OX40 co-stimulation or CTLA-4 blockade can eradicate melanomas containing antigen escape variants. As expected, early on-target recognition of melanoma antigens by tumor-specific CD4 + T cells was required. Surprisingly, complete tumor eradication was dependent on neutrophils and partly dependent on inducible nitric oxide synthase. In support of these findings, extensive neutrophil activation was observed in mouse tumors and in biopsies of melanoma patients treated with immune checkpoint blockade. Transcriptomic and flow cytometry analyses revealed a distinct anti-tumorigenic neutrophil subset present in treated mice. Our findings uncover an interplay between T cells mediating the initial anti-tumor immune response and neutrophils mediating the destruction of tumor antigen loss variants., Competing Interests: Declaration of interests T.M. is a consultant for Daiichi Sankyo, Leap Therapeutics, Immunos Therapeutics, and Pfizer and co-founder of Imvaq Therapeutics. T.M. has equity in Imvaq Therapeutics. T.M. reports grants from Bristol Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics, and Aprea. T.M. is an inventor on patent applications related to work on oncolytic viral therapy, alpha virus-based vaccine, neoantigen modeling, CD40, GITR, OX40, PD-1, and CTLA-4. D.H. and S.B. have received royalties from Agenus. R.Z. is an inventor on patent applications related to work on GITR, PD-1, and CTLA-4; has received grant support from Bristol-Myers Squibb; and is a consultant for Leap Therapeutics. J.D.W. is a consultant for Apricity, Ascentage Pharma, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Dragonfly, Georgiamune, Imvaq, Larkspur, Psioxus, Recepta, Tizona, and Sellas. J.D.W. received grant/research support from Bristol Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Beigene, CellCarta, Imvaq, Linneaus, Larkspur, Georgiamune, Maverick, Tizona Therapeutics, and Xenimmune. J.D.W. is an inventor on the following patents: xenogeneic DNA vaccines, alphavirus replicon particles expressing TRP2, myeloid-derived suppressor cell (MDSC) assay, Newcastle disease virus for cancer therapy, genomic signature to identify responders to ipilimumab in melanoma, engineered vaccinia viruses for cancer immunotherapy (with T.M.), anti-CD40 agonist mAb fused to monophosphoryl lipid A (MPL) for cancer therapy (with T.M.), CAR(+) T cells targeting differentiation antigens as a means to treat cancer, anti-PD-1 antibody, anti-CTLA4 antibodies, anti-GITR antibodies, and methods of use thereof. D.H. and T.M. are co-inventors on patent applications related to OX40 antibodies. M.E. is a member of the research advisory board for brensocatib for Insmed, Inc.; a member of the scientific advisory board for Vividion Therapeutics, Inc.; and a consultant for Protalix, Inc. and holds shares in Agios Pharmaceuticals, Inc., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neutrophils are major effectors and regulators of the immune system. They play critical roles not only in the eradication of pathogens but also in cancer initiation and progression. Conversely, the presence of cancer affects neutrophil activity, maturation, and lifespan. By promoting or repressing key neutrophil functions, cancer cells co-opt neutrophil biology to their advantage. This co-opting includes hijacking one of neutrophils' most striking pathogen defense mechanisms: the formation of neutrophil extracellular traps (NETs). NETs are web-like filamentous extracellular structures of DNA, histones, and cytotoxic granule-derived proteins. Here, we discuss the bidirectional interplay by which cancer stimulates NET formation, and NETs in turn support disease progression. We review how vascular dysfunction and thrombosis caused by neutrophils and NETs underlie an elevated risk of death from cardiovascular events in cancer patients. Finally, we propose therapeutic strategies that may be effective in targeting NETs in the clinical setting., Competing Interests: Declaration of interests M.E. is a member of the research advisory board for brensocatib for Insmed, Inc.; a member of the scientific advisory board for Vividion Therapeutics, Inc.; a consultant for Protalix, Inc.; and holds shares in Agios. She is also a member of the Cancer Cell advisory board. The rest of the authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The EWS-FLI1 fusion oncoprotein deregulates transcription to initiate the paediatric cancer Ewing sarcoma. Here we used a domain-focused CRISPR screen to implicate the transcriptional repressor ETV6 as a unique dependency in this tumour. Using biochemical assays and epigenomics, we show that ETV6 competes with EWS-FLI1 for binding to select DNA elements enriched for short GGAA repeat sequences. Upon inactivating ETV6, EWS-FLI1 overtakes and hyper-activates these cis-elements to promote mesenchymal differentiation, with SOX11 being a key downstream target. We show that squelching of ETV6 with a dominant-interfering peptide phenocopies these effects and suppresses Ewing sarcoma growth in vivo. These findings reveal targeting of ETV6 as a strategy for neutralizing the EWS-FLI1 oncoprotein by reprogramming of genomic occupancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)