Biology subjects

Shelton, M.

Publications and source records attributed to Shelton, M..

5 recordsLinked to original sources

bioRxiv2025

Extracellular vesicles from a model of melanoma cancer-associated fibroblasts induce changes in brain microvascular cells consistent with pre-metastatic niche priming.

Malignant melanoma has one of the lowest 5-year survival rates of any cancer, and is recognised for being particularly invasive and metastatic, with the poorest survival outcomes in brain metastases patients. A key characteristic of these tumours is crosstalk between melanoma cells and cells of the tumour microenvironment (TME), such as cancer associated fibroblasts (CAFs). The role of melanoma-derived small extracellular vesicles (sEVs) in potentiating CAFs has been studied extensively, however the role of CAF sEVs in regulation of the local TME and distal pre-metastatic niche (PMN) is less clear. Here, we demonstrate that sEVs derived from an in vitro model of melanoma CAFs alter melanoma to promote oncogenic parameters within models of the TME and target a model of the brain PMN to promote changes associated with melanoma extravasation. Cargo profiling of these sEVs found significant differential expression of proteins, and RNA associated with pre-metastatic niche remodelling and unfavourable outcomes in patients. Together these data suggest a role for CAF sEVs in local and distal PMN formation, highlighting a potential therapeutic target for metastatic melanoma and identifying prospective liquid biomarker reservoirs.

cancer biology↗

bioRxiv2023

Sex differences in offspring risk and resilience following 11β-hydroxylase antagonism in a rodent model of maternal immune activation

Maternal immune activation (MIA) puts offspring at greater risk for neurodevelopmental disorders associated with impaired social behavior. While it is known that immune signaling through maternal, placental, and fetal compartments contributes to these phenotypical changes, it is unknown to what extent the stress response to illness is involved and how it can be harnessed for potential interventions. To this end, on gestational day 15, pregnant rat dams were administered the bacterial mimetic lipopolysaccharide (LPS; to induce MIA) alongside metyrapone, a clinically available 11{beta}-hydroxylase inhibitor used to treat hypercortisolism in pregnant and neonatal populations. Maternal, placental, and fetal CNS levels of corticosterone and placental 11{beta}HSD enzymes type 1 and 2 were measured 3-hrs post treatment. Offspring social behaviors were evaluated across critical phases of development. MIA was associated with increased maternal, placental, and fetal CNS corticosterone concentrations that were diminished with metyrapone exposure. Metyrapone protected against reductions in placental 11{beta}HSD2 in males only, suggesting that less corticosterone was inactivated in female placentas. Behaviorally, metyrapone-exposure attenuated MIA-induced social disruptions in juvenile, adolescent, and adult males, while females were unaffected or performed worse. Metyrapone-exposure reversed MIA-induced transcriptional changes in monoamine-, glutamate-, and GABA-related genes in the ventral hippocampus of adult males, but not females. Taken together, these findings illustrate that MIA-induced HPA responses act alongside the immune system to produce behavioral deficits. As a clinically available drug, the sex-specific benefits and constraints of metyrapone should be investigated further as a potential means of reducing neurodevelopmental risks due to gestational MIA.

neuroscience↗

bioRxiv2022

Sex-specific role of the circadian transcription factor NPAS2 in opioid tolerance, withdrawal, and analgesia

Opioids like fentanyl are the mainstay treatment for chronic pain. Unfortunately, opioids high addiction liability has led to the current opioid crisis. This is in part related to long-term use side-effects, including analgesic tolerance (gradual decrease in analgesia), and physical dependence (withdrawal symptoms upon opioid interruption), causing dose-escalation and preventing usage interruption. Altered circadian rhythmicity and sleep patterns are common in patients on opioid therapy. Prior research showed intricate bidirectional interactions between circadian rhythmicity, opioid analgesic efficacy, and side-effects. However, underlying mechanisms are largely unknown. Neuronal PAS domain protein 2 (NPAS2) is a circadian transcription factor that is highly expressed in structures of the central nervous system that modulate pain and opioids. In this study, we used male and female mice expressing non-functional NPAS2 (NPAS2 deficient, NPAS2-/-) to investigate the role of NPAS2 in fentanyl analgesia, tolerance, hyperalgesia, and dependence. In NPAS2-/- mice, we found that thermal pain thresholds, acute analgesia, and tolerance to a fixed dose of fentanyl were largely like wild-type mice. However, female NPAS2-/- mice augmented behavioral state of analgesic tolerance and exhibited significantly more behavioral symptoms of physical dependence. Conversely, only male NPAS2-/- mice had increased fentanyl-induced hypersensitivity, when compared to matched-sex littermate controls. Together, our findings suggest sex-specific effects of NPAS2 signaling in the regulation of fentanyl-induced tolerance, hyperalgesia, and dependence.

neuroscience↗

bioRxiv2021

Molecular rhythm alterations in prefrontal cortex and nucleus accumbens associated with opioid use disorder

Severe and persistent disruptions to sleep and circadian rhythms are common features of people with opioid use disorder (OUD). Preclinical findings suggest altered molecular rhythms in the brain are involved in opioid reward and dependence. However, whether molecular rhythms are disrupted in brains of people with OUD remained an open question, critical to understanding the role of circadian rhythms in opioid addiction. We previously used subjects times of death (TOD) as a marker of time of day to investigate transcriptional rhythm alterations in psychiatric disorders. Using TOD and RNA sequencing, we discovered rhythmic transcripts in both the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), key brain areas involved in opioid addiction, were largely distinct between OUD and unaffected comparison subjects. Further, fewer rhythmic transcripts were identified in DLPFC of OUD subjects compared to unaffected subjects, but nearly double the number of rhythmic transcripts were found in the NAc of OUD subjects. In OUD, rhythmic transcripts in the NAc peaked either in the evening or near sunrise, and were associated with dopamine, opioid, and GABAergic neurotransmission. Co-expression network analysis identified several OUD-specific modules in the NAc, enriched for transcripts involved in the modulation of dopamine and GABA synapses, including glutamatergic signaling and extracellular matrices. Integrative analyses with human GWAS revealed that rhythmic transcripts in DLPFC and NAc were enriched for genomic loci associated with sleep duration and insomnia. Overall, our results connect transcriptional rhythm changes in dopamine, opioid, and GABAergic synaptic signaling in human brain to sleep-related phenotypes and OUD.

neuroscience↗

bioRxiv2020

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

BackgroundPrevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA-sequencing (RNA-seq) was conducted on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), regions heavily implicated in OUD, from postmortem brains in subjects with OUD. MethodsWe performed RNA-seq on the DLPFC and NAc from unaffected comparison subjects (n=20) and subjects diagnosed with OUD (n=20). Our transcriptomic analyses identified differentially expressed (DE) transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric ordering (RRHO). Weighted gene co-expression analyses (WGCNA) also identified OUD-specific modules and gene networks. Integrative analyses between DE transcripts and GWAS datasets using linkage disequilibrium score (LDSC) assessed the genetic liability psychiatric-related phenotypes. ResultsRRHO analyses revealed extensive overlap in transcripts between DLPFC and NAc in OUD, primarily relating to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control pro-inflammatory cytokine-mediated, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a critical driver for opioid-induced neuroplasticity. Using LDSC, we discovered genetic liabilities for risky behavior, attention deficit hyperactivity disorder, and depression. ConclusionsOverall, our findings reveal new connections between the brains immune system and opioid dependence in the human brain.

neuroscience↗