MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling.

MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ∼14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only "CD8+ T-cell-inflamed" tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3-4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.

The uptake of Cd, Cr, and Zn by the macroalga Enteromorpha crinita and subsequent transfer to the marine herbivorous rabbitfish, Siganus canaliculatus.

Marine macroalgae can appreciably accumulate metals out of seawater and are the principle food source for marine herbivorous fish, thus playing an important role in introducing metals into marine food webs. There have been few experimental studies on metal transfer from macroalgae up the trophic chain. In this study, we examined the assimilation efficiencies (AEs) of Cd, Cr, and Zn in the rabbitfish, Siganus canaliculatus, which feeds on the macroalga Enteromorpha crinita. The influences of metal concentration and nutrient conditions in the macroalga, and starvation on the assimilation of metals in fish were investigated. The macroalgae were radiolabeled by direct exposure to radiotracers in the dissolved phase. The uptake of metals in the macroalgae proceeded linearly and was directly proportional to the metal concentration in the ambient seawater. Ammonium and nitrate enrichment significantly increased the accumulation of Cd by the macroalgae, whereas Cr accumulation was not influenced by nutrient enrichment. The metal concentrations in the macroalgae did not have any effect on metal assimilation in the rabbitfish. The measured AEs of the metals were generally higher in starved rabbitfish than in fed fish, probably as a result of the prolonged retention of metals in the gut of fish. Rabbitfish fed macroalgae that had been previously exposed to ammonium or nitrate addition decreased their assimilation of Cd and Zn, but not Cr. Phosphate enrichment did not have any significant effect on metal AE in the rabbitfish. Our study demonstrated that marine herbivorous fish can appreciably assimilate trace metals from marine macroalgae and that trophic transfer should be considered as a source for metal accumulation in fish. Nutrient condition and starvation do have considerable effects on the AEs of Cd and Zn in rabbitfish that are fed macroalgae.