Biology subjects

Hong, S. M.

Publications and source records attributed to Hong, S. M..

7 recordsLinked to original sources

bioRxiv2026

Enteric neurons modulate colorectal cancer cell cycle through a PCSK1 - Methionine-Enkephalin Axis

Background and AimsThe tumor microenvironment in colorectal cancer (CRC) is richly innervated, yet the contribution of the enteric nervous system (ENS) to CRC biology remains poorly defined. ENS neurons express proenkephalin (PENK), which can be processed by proprotein convertase 1/3 (PCSK1) to generate Methionine-enkephalin (M-ENK), a bioactive peptide with growth-regulatory potential. We hypothesized that an ENS-derived PCSK1-M-ENK axis restrains CRC proliferation through opioid growth factor receptor (OGFr) signaling and is modulated by stress-associated glucocorticoid receptor (GR) signaling and GLP1 receptor (GLP1R) activity. MethodsPublicly available human CRC single-cell RNA-sequencing datasets were analyzed for OGFr expression. PCSK1 and M-ENK expression in murine ENS and tumor-associated tissue was assessed by immunofluorescence. Functional studies were performed using murine CRC organoids, and primary murine ENS neurons in mono- and co-culture. CRC proliferation was quantified by EdU incorporation following treatment with recombinant M-ENK, recombinant PCSK1, OGFr synthetic ligand naloxone, or PCSK1 inhibitors. Effects of dexamethasone and liraglutide on PCSK1 expression in ENS-containing murine tissue were evaluated. ResultsOGFr was enriched in CRC cells and positively associated with KRAS gene expression. A subset of adult murine colonic myenteric neurons expressed PCSK1 and M-ENK. M-ENK dose-dependently suppressed proliferation of CRC organoid cells. ENS neurons also suppressed CRC proliferation in a PCSK1-dependent manner. Dexamethasone reduced, whereas liraglutide increased, PCSK1 expression. ConclusionsThese findings define a previously unrecognized ENS-derived neuro-oncologic pathway that is associated with reduced CRC cell proliferation and identify the GR/GLP1R-PCSK1-M-ENK axis as a potentially actionable therapeutic node. SummaryThis study identifies a neuronal PCSK1 - M-ENK pathway in the ENS that directly suppresses colorectal cancer growth through local OGFr activation, revealing a previously unrecognized neuropeptidergic mechanism of tumor control within the intestinal microenvironment.

cancer biology↗

bioRxiv2026

Loss of enteric BDNF TrkB signaling and VIPergic dysfunction underlie gastrointestinal dysmotility in a Mecp2-null mouse model of Rett syndrome

Gastrointestinal (GI) dysmotility is a highly prevalent and clinically significant feature of Rett syndrome (RTT), yet its underlying mechanisms remain poorly defined. Here, we investigated these mechanisms of GI dysmotility in a Mecp2-null mouse model of RTT. First, we observed that MeCP2 was expressed in murine myenteric ganglia, including in enteric neurons and that Mecp2-null males developed maturation-associated functional regression in their GI motility. In dysmotile mice, longitudinal muscle-myenteric plexus tissue showed marked reductions in enteric Bdnf isoforms IV, VI, and II, whereas expression of the BDNF receptor isoforms TrkB.FL and TrkB.T1 was not significantly altered, consistent with reduced enteric BDNF-TrkB signaling. Despite impaired GI motility, Mecp2-null mice showed no significant changes in total enteric neuronal density, nitrergic neuronal abundance, or expression of Nos1, Chat, and Uchl1. In contrast, Vip expression was significantly reduced, while expression of VIP receptor genes: Vipr1 and Vipr2 was increased, indicating disrupted VIPergic signaling. Integration with publicly available enteric single-cell/nucleus datasets and targeted qRT-PCR further suggested altered inhibitory neuronal subtype composition, with reduced Vip+ Cartpt+ signatures and increased Nfia expression, suggesting that MeCP2 loss differentially affects distinct inhibitory neuronal subpopulations. Finally, conditional loss of TrkB.FL in neural crest-derived cells reduced Vip expression without recapitulating the full Mecp2-null VIPergic phenotype, indicating that impaired BDNF-TrkB signaling contributes to, but does not completely explain, the GI dysmotility in this model of RTT. Together, these findings identify enteric BDNF-TrkB and VIPergic dysfunction as key mechanisms underlying GI dysmotility in RTT.

neuroscience↗

bioRxiv2025

A novel DNA repair protein, N-Myc downstream regulated gene 1 (NDRG1), links stromal tumour microenvironment to chemoresistance

In pancreatic ductal adenocarcinoma cancer (PDAC) drug resistance is a severe clinical problem and patients relapse within a few months after receiving the standard-of-care chemotherapy. One contributing factor to treatment resistance is the desmoplastic nature of PDAC; the tumours are surrounded by thick layers of stroma composing up to 90% of the tumour mass. This stroma, which is mostly comprised of extracellular matrix (ECM) proteins, is secreted by cancer-associated fibroblasts (CAFs) residing in the tumour microenvironment. However, the mechanistic basis by which the tumour stroma directly contributes to chemoresistance remains unclear. Here, we show that CAF-secreted ECM proteins induce chemoresistance by blunting chemotherapy-induced DNA damage. Mechanistically, we identify N-myc downstream regulated gene 1 (NDRG1) as a key protein required for stroma-induced chemoresistance that responds to signals from the ECM and adhesion receptors. We further show that NDRG1 is a novel DNA repair protein that physically interacts with replication forks, maintains DNA replication and functions to resolve stalled forks caused by chemotherapy. More specifically, NDRG1 reduces R-loops, RNA-DNA hybrids that are known to cause genomic instability. R-loops occur during replication-transcription conflicts in S-phase and after chemotherapy treatments, thus posing a major threat to normal replication fork homeostasis. We identify NDRG1 as highly expressed in PDAC tumours, and its high expression correlates with chemoresistance and poor disease-specific survival. Importantly, knock-out of NDRG1 or inhibition of its phosphorylation restores chemotherapy-induced DNA damage and resensitizes tumour cells to treatment. In conclusion, our data reveal an unexpected role for CAF-secreted ECM proteins in enhancing DNA repair via NDRG1, a novel DNA repair protein, directly linking tumour stroma to replication fork homeostasis and R-loop biology, with important therapeutic implications for restoring DNA damage response pathways in pancreatic cancer. Summary paragraphDrug resistance is a severe clinical problem in stroma-rich tumours, such as pancreatic ductal adenocarcinoma (PDAC), and patients often relapse within a few months on chemotherapy1-9. The stroma, comprised of extracellular matrix (ECM) proteins, is secreted by cancer-associated fibroblasts (CAFs) residing in the tumour microenvironment10-13. Prior work show that ECM proteins provide survival benefits to cancer cells14,15. However, the precise role of CAF-secreted ECM in resistance to DNA damaging chemotherapies remains poorly understood. Here, we link ECM proteins to chemoresistance by enhanced DNA damage repair (DDR). Mechanistically, we identify N-myc downstream-regulated gene 1 (NDRG1) as a key effector downstream of ECM and the integrin-Src-SGK1-signalling axis that mediates enhanced DDR. We show that NDRG1 loss, mutation of conserved His194, or inhibition of NDRG1 phosphorylation by SGK1 lead to replication fork stalling, increased R-loops, and higher transcription-replication conflicts, resulting in genomic instability and sensitivity to chemotherapies. Our analysis of PDAC patient cohorts16 found that high NDRG1 expression correlates with chemoresistance and poor patient survival. In conclusion, we uncover an unexpected role for CAF-secreted ECM proteins in promoting therapeutic resistance by enhancing DDR and establish NDRG1 as a novel DNA repair protein directly linking tumour stroma to DDR.

cancer biology↗

bioRxiv2024

Reduced enteric BDNF-TrkB signaling drives glucocorticoid-mediated GI dysmotility

Stress is a key contributor to gastrointestinal (GI) dysmotility, particularly in patients with disorders of gut-brain interactions (DGBI). Since GI motility is governed by the enteric nervous system (ENS), stress may act by altering ENS function. While stress activates glucocorticoid signaling via the hypothalamic-pituitary-adrenal axis, the impact of stress-mediated glucocorticoid signaling on ENS biology remains poorly understood. In the central nervous system, glucocorticoids reduce specific isoforms of brain-derived neurotrophic factor (BDNF), impairing signaling through its receptor, TrkB, and contributing to behavioral dysfunction. However, the identity of ENS-specific Bdnf isoforms, their glucocorticoid sensitivity, and the effect of enhanced TrkB signaling on GI motility in stressed animals has not been characterized. Here, using male and female mice, we show that >85% of post-natal ENS Bdnf transcripts are glucocorticoid-responsive isoforms. We also demonstrate that both BDNF and its receptor TrkB (Ntrk2) are expressed by enteric neurons. In male mice, stress and administration of dexamethasone--a synthetic glucocorticoid receptor (GR) agonist--cause GI dysmotility, which we demonstrate is associated with significantly reduced Bdnf transcripts in the longitudinal muscle - myenteric plexus (LM-MP) tissue in vivo. Dexamethasone exposure also represses Bdnf transcript and mature protein levels in LM-MP tissue in vitro. Notably, treatment with HIOC, a selective TrkB agonist, rescues GI transit defects in dexamethasone-treated animals. These findings identify BDNF-TrkB signaling as a key modulator of stress-induced ENS dysfunction and highlight TrkB as a promising therapeutic target for GI dysmotility in DGBI. Significance statementHow stress causes gastrointestinal (GI) dysmotility is not well understood. GI motility is regulated by the enteric nervous system (ENS), which is responsive to brain-derived neurotrophic factor (BDNF), which signals through its receptor tropomyosin related kinase B (TrkB). By altering glucocorticoid signaling, stress modulates brains BDNF levels to cause behavioral changes. However, if this pathway is similarly responsible for stresss effects on GI dysmotility is not well understood. Here, by identifying the nature of ENS-specific Bdnf isoforms, studying their response to stress and glucocorticoid signaling, and testing the effect of a TrkB agonist to improve gut motility in a model of glucocorticoid-driven dysmotility, we implicate altered BDNF-TrkB signaling as an important mechanism driving stress-associated dysmotility.

neuroscience↗

bioRxiv2024

Optimization of protocols for immunohistochemical assessment of enteric nervous system in formalin fixed human tissue.

Gastrointestinal (GI) motility is regulated in a large part by the cells of the enteric nervous system (ENS), suggesting that ENS dysfunctions either associate with, or drive GI dysmotility in patients. However, except for select diseases such as Hirschsprungs Disease or Achalasia that show a significant loss of all neurons or a subset of neurons, our understanding of human ENS histopathology is extremely limited. Recent endoscopic advances allow biopsying patients full thickness gut tissues, which makes capturing ENS tissues simpler than biopsying other neuronal tissues, such as the brain. Yet, our understanding of ENS aberrations observed in GI dysmotility patients lags behind our understanding of central nervous system aberrations observed in patients with neurological disease. Paucity of optimized methods for histopathological assessment of ENS in pathological specimens represent an important bottleneck in ascertaining how the ENS is altered in diverse GI dysmotility conditions. While recent studies have interrogated ENS structure in surgically resected whole mount human gut, most pathological specimens are banked as formalin fixed paraffin embedded (FFPE) tissue blocks - suggesting that methods to interrogate ENS in FFPE tissue blocks would provide the biggest impetus for ENS histopathology in a clinical setting. In this report, we present optimized methods for immunohistochemical interrogation of the human ENS tissue on the basis of >25 important protein markers that include proteins expressed by all neurons, subset of neurons, hormones, and neurotransmitter receptors. This report provides a resource which will help pathologists and investigators assess ENS aberrations in patients with various GI dysmotility conditions.

pathology↗

bioRxiv2023

Differences in syncytia formation by SARS-CoV-2 variants modify host chromatin accessibility and cellular senescence via TP53

COVID-19 remains a significant public health threat due to the ability of SARS-CoV-2 variants to evade the immune system and cause breakthrough infections. Although pathogenic coronaviruses such as SARS-CoV-2 and MERS-CoV lead to severe respiratory infections, how these viruses affect the chromatin proteomic composition upon infection remains largely uncharacterized. Here we used our recently developed integrative DNA And Protein Tagging (iDAPT) methodology to identify changes in host chromatin accessibility states and chromatin proteomic composition upon infection with pathogenic coronaviruses. SARS-CoV-2 infection induces TP53 stabilization on chromatin, which contributes to its host cytopathic effect. We mapped this TP53 stabilization to the SARS-CoV-2 spike and its propensity to form syncytia, a consequence of cell-cell fusion. Differences in SARS-CoV-2 spike variant-induced syncytia formation modify chromatin accessibility, cellular senescence, and inflammatory cytokine release via TP53. Our findings suggest that differences in syncytia formation alter senescence-associated inflammation, which varies among SARS-CoV-2 variants.

microbiology↗

bioRxiv2020

Hericerin derivatives from Hericium erinaceus exert BDNF-like neurotrophic activity in central hippocampal neurons and enhance memory

The traditional medicinal mushroom Hericium erinaceus has long been known for enhancing the peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. It was also reported to protect against ageing-dependent cognitive decline in wildtype and in Alzheimers disease mouse models suggesting a yet to be defined action on neurons of the central nervous system. Here, we purified and identified biologically active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom together with its hydrophobic derivative hericene A, were highly potent in inducing extensive axon outgrowth and neurite branching in the absence of serum demonstrating high neurotropic activity. NDPIH also induced enlarged growth cones suggestive of a brain-derived neurotrophic factor (BDNF)-like activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA12 prevented NDPIH-induced neurotrophic activity providing evidence that NDPIH acts via TrkB receptors to mediate its neurotrophic effect in central neurons. Finally, in vivo treatment with H. erinaceus crude extract and hericene A significantly increased BDNF and downstream pathway and enhanced learning and memory in the novel object recognition memory test. Our results suggest that hericene A can promote BDNF-like activity in neurons in vitro and in vivo thereby enhancing recognition memory.

neuroscience↗