Biology subjects

Haley, J.

Publications and source records attributed to Haley, J..

4 recordsLinked to original sources

bioRxiv2025

Low-Intensity Ultrasound Stimulates TAZ in Schwann cells

Mechanosensation, the ability of cells to detect and respond to mechanical forces by transducing them into biochemical signals, is essential for various cellular processes, including morphogenesis, development, tissue homeostasis, and response to injury. In the peripheral nervous system (PNS), Schwann cells play a critical role in nerve development, myelination, and regeneration. These cells are highly responsive to mechanical cues such as tension, compression, and shear forces, which influence their fate, proliferation, differentiation, and regenerative capacity. In this study, we demonstrate that in vitro application of Low Intensity Ultrasound (LIU) transiently increases Schwann cell proliferation. Notably, our results show that LIU selectively activates TAZ, but not YAP, both nuclear transducers of the Hippo pathway. Additionally, we show that the LIU treatment upregulates nerve growth factor (NGF) expression in both Schwann cells and sensory neurons, suggesting a role for LIU in promoting neurotrophic support. This study highlights LIU as a mechanotherapeutic tool that enhances intrinsic regenerative functions in Schwann cells, such as neurotrophic support to neurons via NGF. Main PointsO_LIApplication of LIU promotes SC proliferation and production of nerve growth factors. C_LIO_LITAZ is activated in Schwann cells following LIU application. C_LI

neuroscience↗

bioRxiv2025

Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas

High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

cancer biology↗

bioRxiv2025

Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans, which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.

cell biology↗

bioRxiv2024

Nrf2 orchestrates epigenetic regulations and serves as the master regulator of KLF4 expression and activity during arsenic-induced transformation

Emerging evidence suggests that Nrf2 plays a pro-carcinogenic role in cancer. Our previous study showed that arsenic-induced Nrf2 activation triggers metabolic reprogramming, leading to the formation of cancer stem-like cells. Here, we further demonstrated that KLF4, a key pluripotency factor, is a direct transcriptional target of Nrf2 in arsenic-exposed human bronchial epithelial cells. ChIP-seq analysis identified multiple Nrf2 binding peaks at the Klf4 gene locus, which overlap with the enhancer markers H3K4me1 and H3K27Ac. Nrf2 knockout reduced both KLF4 expression and enhancer marker enrichment, accompanied by a global decrease in KLF4 binding across the genome. In wild-type (WT) cells, arsenic treatment increased KLF4 binding on genes involved in oncogenic pathways such as STAT3, SOX2, Nrf2, cell growth, Hedgehog, and EMT. We also found that KLF4 engages in a self-feedback loop in response to Nrf2 signaling. Lastly, our data showed that the co-occupancy of Nrf2 and KLF4 is crucial for establishing active enhancer hubs in the genome. These findings suggest that Nrf2s oncogenic effects are, in part, mediated by Nrf2 dependent self-amplification of KLF4 expression and function. Thus, targeting both Nrf2 and KLF4 could be a promising therapeutic strategy for eliminating cancer stem-like cells.

cancer biology↗