To mitigate melanoma risk, sunscreen use is widely advocated; yet, the ability of sunscreens to prevent melanoma remains controversial. Here, we test the tenet that sunscreens limit melanoma risk by blocking ultraviolet radiation (UV)-induced DNA damage using murine models that recapitulate the genetics and spontaneous evolution of human melanoma. We find that a single, non-erythematous dose of UV dramatically accelerates melanoma onset and increases tumor multiplicity in mice carrying an endogenous, melanocyte-specific NRas allele. By contrast, transient UV exposure does not alter tumor onset in mice lacking p16 or harboring an NRas allele. To block the rapid onset of melanoma cooperatively caused by UV and NRas , we employed a variety of aerosol sunscreens. While all sunscreens delayed melanoma formation and blocked UV-induced DNA damage, differences in aerosol output (i.e., amount applied/cm ) caused variability in the cancer preventative efficacy of products with identical sunburn protection factor (SPF) ratings.

A distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma. We generate eight conditional, knock-in mouse models and show that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation, whereas common melanoma mutants (NRAS Q61R, Q61K, or Q61L) induce rapid tumor onset with high penetrance. Molecular dynamics simulations, combined with cell-based protein–protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.

Congenital tracheomalacia, resulting from incomplete tracheal cartilage development, is a relatively common birth defect that severely impairs breathing in neonates. Mutations in the Hedgehog (HH) pathway and downstream Gli transcription factors are associated with tracheomalacia in patients and mouse models; however, the underlying molecular mechanisms are unclear. Using multiple HH/Gli mouse mutants, including one that mimics Pallister–Hall Syndrome, we show that excessive Gli repressor activity prevents specification of tracheal chondrocytes. Lineage-tracing experiments show that Sox9+ chondrocytes arise from HH-responsive splanchnic mesoderm in the fetal foregut that expresses the transcription factor Foxf1. Disrupted HH/Gli signaling results in (1) loss of Foxf1, which in turn is required to support Sox9+ chondrocyte progenitors, and (2) a dramatic reduction in Rspo2, a secreted ligand that potentiates Wnt signaling known to be required for chondrogenesis. These results reveal an HH-Foxf1-Rspo2 signaling axis that governs tracheal cartilage development and informs the etiology of tracheomalacia.This article has an associated First Person interview with the first author of the paper.

Background: The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T lymphocytes (PBTLs), biologic aging is characterized by changes in T-cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown. Methods: We prospectively collected PBTLs from 117 cancer-free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. Seventy-four mRNAs indicative of T-cell subset, activation, costimulation/inhibition, and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on logtransformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year. Results: Fifteen mRNAs correlated with chronologic age in controls, including markers of T-cell subset, differentiation, cytokine production, and costimulation/inhibition. None of these mRNAs remained correlated with age in patients. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.