Somatic gain-of-function mutations of GNAQ and GNA11, which encode α subunits of heterotrimeric Gα_q/11 proteins, occur in about 85% of cases of uveal melanoma (UM), the most common cancer of the adult eye. Molecular therapies to directly target these oncoproteins are lacking, and current treatment options rely on radiation, surgery, or inhibition of effector molecules downstream of these G proteins. A hallmark feature of oncogenic Gα_q/11 proteins is their reduced intrinsic rate of hydrolysis of guanosine triphosphate (GTP), which results in their accumulation in the GTP-bound, active state. Here, we report that the cyclic depsipeptide FR900359 (FR) directly interacted with GTPase-deficient Gα_q/11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase Cβ (PLCβ) signaling driven by these oncogenes. Thereby, FR suppressed the proliferation of melanoma cells in culture and inhibited the growth of Gα_q-driven UM mouse xenografts in vivo. In contrast, FR did not affect tumor growth when xenografts carried mutated B-Raf^V600E as the oncogenic driver. Because FR enabled suppression of malignant traits in cancer cells that are driven by activating mutations at codon 209 in Gα_q/11 proteins, we envision that similar approaches could be taken to blunt the signaling of non-Gα_q/11 G proteins.

Mast cells (MCs) are best-known as key effector cells of immediate-type allergic reactions that may even culminate in life-threatening anaphylactic shock syndromes. However, strategically positioned at the host–environment interfaces and equipped with a plethora of receptors, MCs also play an important role in the first-line defense against pathogens. Their main characteristic, the huge amount of preformed proinflammatory mediators embedded in secretory granules, allows for a rapid response and initiation of further immune effector cell recruitment. The same mechanism, however, may account for detrimental overshooting responses. MCs are not only detrimental in MC-driven diseases but also responsible for disease exacerbation in other inflammatory disorders. Focusing on the skin as the largest immune organ, we herein review both beneficial and detrimental functions of skin MCs, from skin barrier integrity via host defense mechanisms to MC-driven inflammatory skin disorders. Moreover, we emphasize the importance of IgE-independent pathways of MC activation and their role in sustained chronic skin inflammation and disease exacerbation.

Background: Psoriasis is associated with a significant comorbidity burden, especially cardiovascular and metabolic complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, used to treat obesity and diabetes, could potentially reduce comorbidities in patients with psoriasis. Objectives: To investigate all-cause mortality, cardiovascular, inflammatory and psychiatric outcomes, and adverse events in patients with psoriasis treated with GLP-1RAs. Methods: This retrospective population-based cohort study used real-world data from the US TriNetX database. Patients with psoriasis who were treated for diabetes or obesity with a GLP-1RA during the follow-up period of 2 years were compared with those treated with other systemic antidiabetic or antiobesity drugs. After 1 : 1 propensity score matching for relevant risk factors, 3048 participants were included in each cohort. Primary outcomes included the risk of cardiometabolic, psychiatric and autoimmune sequelae of psoriasis, as well as all-cause mortality and potential adverse drug events. The analysis was repeated using cohorts without psoriasis and the results were further validated through two sensitivity analyses involving (i) later follow-up periods or (ii) the exclusion of patients with pustular psoriasis. Results: In the matched cohorts of 3048 patients with psoriasis treated with a GLP-1RA [60.4% women, mean (SD) age 56.94 (12.02) years] vs. other antidiabetic and antiobesity drugs [61.9% women, mean (SD) age 56.42 (14.16) years], GLP-1RA treatment was associated with significantly decreased all-cause mortality [hazard ratio (HR) 0.219, 95% confidence interval (CI) 0.123–0.391; P < 0.001] and reduced risk of major adverse cardiac events (HR 0.561, 95% CI 0.442–0.714; P < 0.001). Additionally, lower risks for alcohol (HR 0.346, 95% CI 0.174–0.685; P = 0.009) and substance abuse (HR 0.510, 95% CI 0.350–0.743; P = 0.002) were found. Typical adverse drug events were not more frequent in the GLP-1RA cohort. The risk reductions were more pronounced in the cohorts with psoriasis than in those with obesity or diabetes without psoriasis. The findings were consistent across all sensitivity analyses. Conclusions: GLP-1RA treatment was safe and associated with reduced risks of cardiovascular and psychiatric comorbidities, as well as lower mortality in patients with psoriasis, with risk reductions markedly higher than in cohorts without psoriasis. Physicians should consider this drug class for patients with psoriasis and comorbid obesity or diabetes.

The aryl hydrocarbon receptor (AHR) is a ligand binding‐transcription factor of the basic helix‐loop‐helix family regulating multiple cellular functions such as differentiation, cell cycle, apoptosis, and inflammatory reactions. In neoplastic diseases, the AHR has been described to modulate proliferation and differentiation in dichotomous ways, either inhibiting or augmenting the growth of tumors. The precise role of AHR in melanoma is mostly unknown. Here, we report a functional effect of AHR activation on inflammation‐induced melanoma cell dedifferentiation and the development of lung metastases in a mouse model. Via in silico analyses of “The Cancer Genome Atlas” human melanoma cohort, we detected a correlation between AHR expression levels and a dedifferentiated melanoma cell phenotype with an invasive gene signature, which we were able to functionally recapitulate in a panel of human melanoma cell lines. Both human and mouse melanoma cell lines upregulated AHR expression after inflammatory stimulation with tumor necrosis factor‐α (TNF‐α). Activation of AHR in human and mouse melanoma cell lines with the endogenous ligand formylindolo(3,2‐b)carbazole (FICZ) promoted inflammation‐induced dedifferentiation in vitro. Importantly, mouse melanoma cells with CRISPR/Cas9‐mediated disruption of the AHR gene showed impaired in vivo tumor growth after transplantation in the skin as well as decreased numbers of spontaneous lung metastases. Taken together, our results demonstrate a functional role for AHR expression in melanoma development and metastatic progression. This provides a scientific basis for future experiments that further dissect the underlying molecular mechanisms and assess the potential for AHR inhibition as part of multimodal melanoma treatment strategies.

Inflammatory diseases of the skin, including atopic dermatitis and psoriasis, have gained increasing attention with rising incidences in developed countries over the past decades. While bodily properties, such as immunological responses of the skin, have been described in some detail, interactions with the brain via different routes are less well studied. The suggested routes of the skin–brain axis comprise the immune system, HPA axis, and the peripheral and central nervous system, including microglia responses and structural changes. They provide starting points to investigate the molecular mechanisms of neuropsychiatric comorbidities in AD and psoriasis. To this end, mouse models exist for AD and psoriasis that could be tested for relevant behavioral entities. In this review, we provide an overview of the current mouse models and assays. By combining an extensive behavioral characterization and state-of-the-art genetic interventions with the investigation of underlying molecular pathways, insights into the mechanisms of the skin–brain axis in inflammatory cutaneous diseases are examined, which will spark further research in humans and drive the development of novel therapeutic strategies.

Mast cells (MCs) are best known as key effector cells of immediate type allergic reactions that may even culminate in life-threatening anaphylactic shock syndromes. However, strategically positioned at host-environment interfaces and equipped with a plethora of receptors, MCs also play an important role in the first line defense against pathogens. Their main characteristic, the huge amount of preformed pro-inflammatory mediators embedded in secretory granules, allow for a rapid response and initiation of further immune effector cell recruitment. The same mechanism, however, may account for detrimental overshooting responses. MCs are not only detrimental in MC-driven diseases, but also responsible for disease exacerbation in other inflammatory disorders. Focusing on the skin as the largest immune organ, we herein review both beneficial and detrimental functions of skin MCs all the way from skin barrier integrity via host defense mechanisms to MC-driven inflammatory skin disorders. Moreover, we emphasize the importance of IgE-independent pathways of MC activation and their role in sustained chronic skin inflammation and disease exacerbation.