Biology subjects

Arai, J.

Publications and source records attributed to Arai, J..

5 recordsLinked to original sources

bioRxiv2026

A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis

The gastroesophageal junction (GEJ) is continuously exposed to refluxed bile acids and microbial perturbations, yet how these environmental cues are converted into persistent oncogenic signaling is unknown. Here we show that bile acid remodeling enriches the oral commensal Prevotella melaninogenica at the GEJ, where bacterial succinate activates both vagal sensory neurons and SUCNR1-expressing tuft cells. Activated tuft cells release 15-deoxy-12,14-prostaglandin J2 (15-d-PGJ2), which sensitizes sensory neurons and sustains nerve remodeling, while neuronal CGRP drives expansion and tuft-cell differentiation of neuro-responsive epithelial progenitors through RAMP1. This self-reinforcing microbiota-neuron-epithelium circuit promotes dysplastic progression, and its genetic or pharmacological disruption, including with the approved CGRP antagonist rimegepant, suppresses tumor development, revealing an interceptable mechanism linking environmental dysbiosis to cancer initiation through neural circuits.

cancer biology↗

bioRxiv2026

Sensory neurons encode long-term inflammatory memory that promotes gastric regeneration and tumorigenesis

Inflammatory memory has emerged as a fundamental principle by which prior injury shapes future tissue responses, yet whether sensory neurons participate in long-term tissue memory remains unknown. Here, we show that vagal sensory neurons acquire a durable, experience-dependent state following gastric injury or Helicobacter pylori infection, leading to enhanced regeneration, metaplasia, and tumor progression upon re-injury. This neuronal program is stable, functionally transferable, and sufficient to drive epithelial responses in vivo. Mechanistically, injury-activated ILC2s establish sensory neuronal memory through IL-13-dependent epigenetic remodeling, inducing SMYD4-mediated H3K4 trimethylation and promoting CGRP-dependent activation of gastric epithelial cells. Together, our findings support a model in which tissue memory is not restricted to epithelial or immune compartments but emerges through coordinated long-term adaptations across multiple cellular systems. Within this framework, sensory neurons provide a persistent substrate for recall responses, linking prior inflammatory experience to sustained epithelial plasticity and cancer susceptibility. HIGHLIGHTSO_LISensory neurons function as a durable compartment of tissue memory. C_LIO_LICGRP-RAMP1 signaling couples neuronal memory to gastric stem cells. C_LIO_LIILC2-derived IL-13 establishes sensory neuronal memory programs. C_LIO_LISMYD4-mediated H3K4me3 stabilizes long-term neuronal memory. C_LIO_LINeuronal memory promotes gastric regeneration and tumor susceptibility. C_LI

cancer biology↗

bioRxiv2025

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified Ntn1 upregulation, and then verified its in vivo upregulation during pancreatic tumorigenesis in humans and mice. NTN1 and its receptor NEO1 were upregulated in epithelial cells by the Kras mutation and {beta}-adrenergic signaling, in part, through the MAPK pathway. Ex-vivo culture of celiac ganglia showed that NTN1 promoted the axonogenesis of sympathetic neurons through the nerve NEO1 receptor. In the Pdx1-Cre;LSL-KrasG12D/+ model, Ntn1 knockout decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant NTN1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of PDAC (pancreatic ductal adenocarcinoma), treatment with a NTN1-neutralizing antibody or tumoral knockdown of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, Ntn1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the NTN1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the NTN1/NEO1 axis could represent a potential therapeutic approach for PDAC. Statement of SignificanceNTN1 promotes pancreatic tumorigenesis and metastasis directly and indirectly through nerves, highlighting the importance of tumor cell-nerve crosstalk in cancer. NTN1 blockade could represent a promising strategy for treating PDAC liver metastasis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/666009v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@ca611corg.highwire.dtl.DTLVardef@ad9264org.highwire.dtl.DTLVardef@1661c00org.highwire.dtl.DTLVardef@b86798_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Muc6-expressing gastric isthmus progenitors contribute to regeneration and metaplasia supported by myeloid-mesenchymal interactions

Gastric mucosal homeostasis is maintained by tissue-resident stem and progenitor cells residing in the isthmus region. Following mucosal injury, surviving cells contribute to regeneration, coinciding with characteristic pathological changes such as atrophic gastritis and metaplasia. To comprehensively understand the cellular dynamics involved in this process, we performed single-cell and spatial transcriptomics using newly generated transgenic mice. In human samples and mouse models, loss of gastric chief cells precedes, and even induces, loss of parietal cells during the progression of atrophy and metaplasia, validating the causal relationship underlying the decrease of these two lineages. Single-cell analysis confirmed robust stemness and metaplastic changes in the Muc6-expressing neck lineage following either chief or parietal cell ablation, and lineage-tracing experiments revealed that Muc6-expressing isthmus progenitors serve as a source of metaplasia and regeneration. Mechanistically, mucosal injury recruits IL-1-expressing myeloid cells, which stimulates NRG1 production in stromal fibroblasts, leading to mucosal proliferation and regeneration mediated by Myc activation in isthmus progenitors. These findings highlight the injury-responsible stem cell-like function of Muc6-expressing isthmal progenitors, which play a critical role in mucosal homeostasis and disease progression. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/648856v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@10fc2eaorg.highwire.dtl.DTLVardef@1c5b82corg.highwire.dtl.DTLVardef@1be747dorg.highwire.dtl.DTLVardef@d1d722_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Plasma irradiation efficiently inactivates the coronaviruses mouse hepatitis virus and SARS-CoV-2

Many inactivation methods have been shown to inactivate SARS-CoV-2 for safe and efficient diagnostic methods. COVID-19 is caused by airborne infection of SARS-CoV-2, and therefore, methods of inactivating the virus efficiently and safely are crucial for reducing the risk of airborne infection. In this regard, the effect of plasma discharge on the infectivity of the coronaviruses mouse hepatitis virus (MHV) and SARS-CoV-2 was tested. Plasma discharge efficiently reduced the infectivity of both coronaviruses. Treatment of SARS-CoV-2 in culture medium with a plasma discharge resulted in 95.17% viral inactivation after plasma irradiation after 1 hour (hr), 99.54% inactivation after 2 hrs and 99.93% inactivation after 3 hrs. Similar results were obtained for MHV. The results indicated that plasma discharge effectively and safely inactivated the airborne coronaviruses and may be useful in minimizing the risk of airborne infection of SARS-CoV-2.

microbiology↗