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Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFR hi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma., (© 2023. The Author(s).)

Lipids have essential biological functions in the body (e.g., providing energy storage, acting as a signaling molecule, and being a structural component of membranes); however, an excess of lipids can promote tumorigenesis, colonization, and metastatic capacity of tumor cells. To metastasize, a tumor cell goes through different stages that require lipid-related metabolic and structural adaptations. These adaptations include altering the lipid membrane composition for invading other niches and overcoming cell death mechanisms and promoting lipid catabolism and anabolism for energy and oxidative stress protective purposes. Cancer cells also harness lipid metabolism to modulate the activity of stromal and immune cells to their advantage and to resist therapy and promote relapse. All this is especially worrying given the high fat intake in Western diets. Thus, metabolic interventions aiming to reduce lipid availability to cancer cells or to exacerbate their metabolic vulnerabilities provide promising therapeutic opportunities to prevent cancer progression and treat metastasis., Competing Interests: Declaration of interests S.A.B. is the co-founder of ONA Therapeutics., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Fatty acid uptake and altered metabolism constitute hallmarks of metastasis 1,2 , yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood 3,4 . Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The purpose of this study was to compare in-hospital time, medical costs, and patient satisfaction before and after the introduction of a nurse practitioner in a chronic heart failure clinic. The records of all patients who attended the NP chronic congestive heart failure clinic were reviewed. Questionnaires were mailed to all available patients to evaluate satisfaction. We compared the number of hospitalizations, inpatient hospital days, and total yearly cost, 1 year before and 1 year after the institution of the chronic congestive heart failure clinic. Fifteen patients were seen an average of every 3 weeks for 7 to 48 months for a mean follow-up period of 24 months. Ages ranged from 48 to 86 years, for a mean age of 65. All but three patients had class IV congestive heart failure. Twelve patients had coronary disease, two valvular heart disease and one congestive cardiomyopathy. Seven of the 15 patients died during the follow-up period, all but one of progressive congestive heart failure. The number of yearly hospitalizations per patient decreased from 2.8 to 0.7 and yearly hospitalized days per patient from 62 to 9 (p less than .01). Total yearly medical cost decreased $131,175. Patient satisfaction was unanimous. In-hospital time and yearly medical costs decreased markedly and patient satisfaction increased after institution of the NP chronic congestive heart failure clinic.