Biology subjects

Peterson, E. R.

Publications and source records attributed to Peterson, E. R..

5 recordsLinked to original sources

bioRxiv2024

Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance. Here, we find that radiation acutely increases the levels of methionine-related metabolites in a variety of treatment-resistant GBM models. Stable isotope tracing studies further revealed that radiation acutely activates methionine to S-adenosyl methionine (SAM) conversion through an active signaling event mediated by the kinases of the DNA damage response. In vivo tumor SAM synthesis increases after radiation, while normal brain SAM production remains unchanged, indicating a tumor- specific metabolic alteration to radiation. Pharmacological and dietary strategies to block methionine to SAM conversion slowed DNA damage response and increased cell death following radiation in vitro. Mechanistically, these effects are due to depletion of DNA repair proteins and are reversed by SAM supplementation. These effects are selective to GBMs lacking the methionine salvage enzyme methylthioadenosine phosphorylase. Pharmacological inhibition of SAM synthesis hindered tumor growth in flank and orthotopic in vivo GBM models when combined with radiation. By contrast, methionine depletion does not reduce tumor SAM levels and fails to radiosensitize intracranial models, indicating depleting SAM, as opposed to simply lowering methionine, is critical for hindering tumor growth in intracranial models of GBM. These results highlight a new signaling link between DNA damage and SAM synthesis and define the metabolic fates of methionine in GBM in vivo. Inhibiting radiation-induced SAM synthesis slows DNA repair and augments radiation efficacy in GBM. Using MAT2A inhibitors to deplete SAM may selectively overcome treatment resistance in GBMs with defective methionine salvage while sparing normal brain.

cancer biology↗

bioRxiv2024

Inhibition of H3K27M-enhanced ATM signaling increases radiation efficacy in diffuse midline glioma

H3K27-altered diffuse midline glioma (DMG) is an aggressive and treatment-resistant form of pediatric high-grade glioma (pHGG). The disease is defined by point mutations in histone H3 that convert lysine 27 to methionine (termed H3K27M), resulting in genome-wide epigenetic changes that drive tumorigenesis. While radiation therapy is the standard of care, subsequent recurrence, often within the high dose radiation field, is universal. We found that the apical DNA damage response (DDR) kinase Ataxia Telangiectasia-Mutated (ATM) was uniquely upregulated in H3K27M-expressing patient tumor samples compared to pHGG expressing only wild-type histone H3. Using a panel of H3K27 isogenic DMG cell lines, we further found that H3K27M was associated with reduced H3K27me3 within the ATM promoter, increased ATM mRNA levels, and elevated DDR signaling, even in the absence of exogenous DNA damage. Consistent with these results, AZD1390, a clinical-grade, CNS-penetrant ATM inhibitor, sensitized H3K27M neurospheres to the long-term effects of radiation on survival, in part due to attenuated repair of radiation-induced DNA damage. Finally, AZD1390 sensitized orthotopic H3K27M mutant tumors to radiotherapy and significantly extended median survival relative to vehicle, AZD1390 or radiation alone (50 days vs 31, 36 or 39 days, respectively) with minimal adverse effects. Taken together, these data provide a direct mechanistic link between the H3K27M mutation and ATM expression and support the clinical investigation of AZD1390 with radiotherapy in H3K27M-altered DMG.

cancer biology↗

bioRxiv2023

Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability

Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state. We found that early gestational Fib-iNs grew longer neurites than all other ages, mirroring the developmental switch in regenerative ability in rodents. RNA-sequencing and screening revealed ARID1A as a developmentally-regulated modifier of neurite growth in human neurons. These data suggest that age-specific epigenetic changes may drive the intrinsic loss of neurite growth ability in human CNS neurons during development. One-Sentence Summary: Directly-reprogrammed human neurons demonstrate a developmental decrease in neurite growth ability.

neuroscience↗

bioRxiv2023

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

cancer biology↗

bioRxiv2022

Reading instruction causes changes in category-selective visual cortex

Education sculpts specialized neural circuits for skills like reading that are critical to success in modern society but were not anticipated by the selective pressures of evolution. Does the emergence of brain regions that selectively process novel visual stimuli like words occur at the expense of cortical representations of other stimuli like faces and objects? To answer this question we conducted a randomized controlled trial with pre-school children (five years of age). We found that being taught reading versus oral language skills induced different patterns of change in category-selective regions of visual cortex. Reading instruction enhanced the response to text but did not diminish the response to other categories. How these changes play out over a longer timescale is still unknown but, based on these data, we can surmise that high-level visual cortex undergoes rapid changes as children enter school and begin establishing new skills like literacy.

neuroscience↗