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Maas, L.

Publications and source records attributed to Maas, L..

4 recordsLinked to original sources

A targetable dependency on nonsense-mediated decay for proteostasis and immune control in small cell lung cancer

Small cell lung cancer (SCLC) is among the deadliest cancers with excessive somatic alterations, expectedly resulting in immunogenic epitopes. However, patient benefit from immunotherapy is limited. We found abundant frameshift mutations in SCLC, regarded as highly immunogenic, counterbalanced by a hyperactive nonsense-mediated decay (NMD) pathway, responsible for frameshift-mRNA degradation. NMD activity correlated with tumor mutational burden (TMB) across cancers, suggesting that SCLC depends on NMD for cellular homeostasis and immune evasion. NMD inhibition impaired SCLC proliferation and induced ER stress-dependent apoptosis in a TMB-dependent manner, thereby enabling pharmacological inhibition in vivo which effectively controlled tumor growth. By integrating genome and transcriptome sequencing with MHC-I immunopeptidomics and functional in vitro and in vivo assays, we identified that NMD inhibition boosted neoantigen expression and presentation by tumor cells and increased T cell recognition, thus enhancing overall tumor immunogenicity and further improving immunotherapy efficacy in vivo. Our work shows that SCLC - as a TMBhigh cancer - relies on NMD for survival and immune escape, uncovering a novel TMB-dependent tractable vulnerability for this devastating disease.

cancer biology↗

Prolonged impact of fire on peatland fungi despite rapid recovery of vegetation, prokaryotes, and soil physicochemistry

Climate change is increasing the frequency of wildfires in ecosystems that historically rarely burn, such as wet heaths and peatlands, thereby threatening carbon storage, biodiversity, and ecosystem functioning. We conducted a three-year, multi-level study to assess early post-fire recovery trajectories of soil physicochemical properties, vegetation, and soil microbial communities in a wet peatland-heathland mosaic affected by a flaming wildfire. Using a paired-plot design of burned and adjacent intact plots, we observed immediate spikes in bioavailable nitrogen (NH, NO-) and phosphorus (POlsen) and a reduction in soil moisture in burned plots, yet two years later these parameters had normalized, indicating rapid abiotic recovery. Vegetation was also strongly altered in the year of the fire, quantifiable by a distinct destruction of herb, moss, tree and litter cover. Although initial regrowth was dominated by a relatively fast resprouting of the graminoid Molinia caerulea, its absolute cover in burned plots never exceeded its cover in intact plots, suggesting this species did not expand post-fire. More typical peatland and wet heath species, including ericoid shrubs and Sphagnum mosses, recovered more gradually but largely returned to pre-fire levels within the timespan of our study, highlighting high vegetation resilience. Soil microbial communities showed contrasting responses. Prokaryotic communities shifted immediately after burning but largely recovered within one year. Fungal communities, however, exhibited stronger and more persistent changes and followed a distinct recovery trajectory shaped by succession of immediate and delayed fungal responders. Overall, pyrophilous and fire-tolerant fungi, such as Coniochaeta spp., increased, as did many presumably generalist or opportunistic saprotrophs. Litter and wood-associated saprotrophs as well as many mycorrhizal taxa, however, declined. Ongoing fungal shifts occurred even after soil chemistry and vegetation had largely returned to baseline, reflecting a temporary decoupling between above- and belowground communities that may have cascading effects on ecosystem functioning. In conclusion, our results reveal differential recovery trajectories across the soil-microbiome-vegetation interface and highlight that seemingly rapid abiotic and aboveground biotic recovery can mask prolonged microbial disruptions. We emphasize the importance of multi-level assessments for understanding ecosystem resilience. HighlightsO_LISoil physicochemistry, vegetation and prokaryotes recovered rapidly after a peatland wildfire C_LIO_LIFungal communities lagged behind and followed a slower recovery trajectory C_LIO_LIThe timing and duration of fungal responses to fire varied across taxa and included immediate or delayed as well as short-lived or persistent responders C_LIO_LIThere was a mismatch between vegetation and fungal recovery trajectories, evidenced by a transient post-disturbance decoupling between above- and belowground biotic communities C_LIO_LIPresumed aboveground recovery can mask prolonged belowground disruptions, with potential implications for decomposition, nutrient cycling, and plant-microbe interactions C_LI

ecology↗

Double stranded RNA sensing drives interferon silencing in early development

In early mammalian development, the type I interferon (IFN) response is inactive, only becoming functional after gastrulation. As a result, the totipotent and pluripotent embryonic stages remain highly susceptible to pathogens, including viruses. Here, we show that pluripotent mouse embryonic stem cells (mESCs) suppress the RIG-I-like receptor sensing pathway by silencing the expression of the dsRNA sensor MDA5. We show that this silencing is required to avoid the recognition of dsRNAs from endogenous origin, which only accumulate in mESCs. Reintroducing MDA5 results in recognition of these endogenous dsRNAs, and activation of the IFN response through IRF3. The production of IFN alters the differentiation ability of mESCs, as well as the pluripotency gene expression program, as shown by epigenetic, transcriptomic and proteomic analyses. These findings are conserved in zebrafish, where MDA5 is also expressed at later stages of development. Similarly, zebrafish lack early-stage IFN activation and premature IFN signalling results in developmental defects. Altogether, we conclude that silencing the RIG-I-like receptor pathway during early development is the widely conserved and is required to prevent aberrant immune recognition of endogenous dsRNAs, safeguarding normal development.

cell biology↗

Rewired type I IFN signaling is linked to age-dependent differences in COVID-19

Advanced age is the most important risk factor for severe disease or death from COVID-19, but a thorough mechanistic understanding of the molecular and cellular underpinnings is lacking. Multi-omics analysis of samples from SARS-CoV-2 infected persons aged 1 to 84 years, revealed a rewiring of type I interferon (IFN) signaling with a gradual shift from signal transducer and activator of transcription 1 (STAT1) to STAT3 activation in monocytes, CD4+ T cells and B cells with increasing age. Diversion of interferon IFN signaling was associated with increased expression of inflammatory markers, enhanced release of inflammatory cytokines, and delayed contraction of infection-induced CD4+ T cells. A shift from IFN-responsive germinal center B (GCB) cells towards CD69high GCB and atypical B cells corresponded to the formation of IgA in children while complement fixing IgG was dominant in adults. Our data provide a mechanistic basis for inflammation-prone responses to infections and associated pathology during aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/619479v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@723896org.highwire.dtl.DTLVardef@e12b2aorg.highwire.dtl.DTLVardef@d8de22org.highwire.dtl.DTLVardef@1df96ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗