Swanson, M. R. | bioRxiv Science

bioRxiv2025

Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer

N-Nitrosodimethylamine (NDMA), a probable human carcinogen, induces toxic and mutagenic O6-methylguanine lesions that are repaired by the O6-methylguanine methyltransferase (MGMT). To elucidate mechanisms of NDMA-induced liver cancer progression, we performed longitudinal analyses of phenomic, transcriptomic, and phosphoproteomic changes in wild-type and MGMT-deficient mice, observing amplified responses in the deficient genotype. Early molecular rewiring indicative of a DNA damage response was detected by phosphoproteomic and transcriptomic profiling within days post-exposure. Transcriptomic analyses identified a persistent and robust interferon response as the dominant activated pathway. This chronic interferon signaling, which remained unresolved, correlated with extensive clonal expansion, an early hallmark of oncogenesis. Spatial transcriptomics further revealed pathway alterations favoring tumorigenesis within clonally expanded cells. These findings delineate the cascade of molecular events triggered by acute early-life NDMA exposure, culminating in cancer development months later. Our study unveils potential predictive biomarkers and strategies for disease mitigation.

cancer biology↗

bioRxiv2025

Less is More: Lower Levels of Task-Induced Hippocampal Activation Predict Better Performance on a Separate Verbal Memory Evaluation

Memories that differ in content or duration differ in the extent to which they depend on the hippocampus, and also the part of the hippocampus, posterior (pHPC) or anterior (aHPC), that they implicate. Inter-individual differences in learning-related activation in different hippocampal subregions have been found to predict specific differences in memory abilities. The complexity of these relationships creates a setting that is ripe for theoretically informative investigation, but that can also lead to reports of spurious relationships that do not reflect underlying neurobiological associations. Across-study replication is therefore a critical first step toward understanding how differences in hippocampal activity drive individual differences in memory ability. In the domain of verbal memory, Wig et al. (2008) identified a negative relationship between task-induced activation in pHPC and out-of-scanner verbal memory test performance. Replicating this result in an independent sample of 86 participants, we identified the same negative correlation between pHPC activation during a Lithuanian word learning task and out-of-scanner California Verbal Learning Test (CVLT-II) performance. This replication represents a critical step toward understanding how pHPC supports verbal memory by answering the basic question of whether the relationship can be reliably observed.

neuroscience↗