Biology subjects

Zhang, X.-L.

Publications and source records attributed to Zhang, X.-L..

7 recordsLinked to original sources

bioRxiv2026

Stromal control of sympathetic rewiring in metastatic lymph nodes

Metastatic lymph nodes (LNs) are dynamically remodeled tissues, but this process has been understood mainly in immune and stromal terms. We show that tumor-driven LN remodeling also involves adaptive neural rewiring. In a mouse model of nodal metastasis, sympathetic fibers, but not sensory fibers, progressively expanded during LN remodeling and tracked with metastatic progression. Fibroblastic reticular cells (FRCs) adopted a neuro-supportive program characterized by increased hepatocyte growth factor (HGF) production, while local stromal HGF acted through MET on sympathetic neurons to stimulate neurite outgrowth. Increased substrate stiffness enhanced FRC activation and HGF production, suggesting that mechanical remodeling may reinforce the neuro-supportive stromal state. Inhibition of HGF signaling or ablation of sympathetic innervation reduced LN enlargement and nodal tumor burden. These findings identify neural plasticity as a functional component of the metastatic LN niche and reveal a stromal/mechanical/neural framework that supports metastatic LN progression.

cancer biology↗

bioRxiv2025

A neuroendocrine principle: Pancreatic islets actively shape sympathetic innervation

Survival critically depends on maintaining blood glucose levels to provide essential energy, especially during emergencies such as the fight-or-flight response, when timely glucose control via neural integration is vital. However, pancreatic islets constitute only a small fraction of the pancreas and are dispersed throughout the organ, raising the fundamental question of how the nervous system coordinates synchronized control of multiple islets. Using whole-organ clearing and 3D imaging, we mapped pancreatic sympathetic innervation, revealing specialized anatomical integration between sympathetic nerves and islets. Transplanted islets intrinsically attracted sympathetic nerves independent of their native environment. Chronic islet injury disrupted sympathetic innervation and markedly impaired nerve regeneration after denervation. Sympathetic denervation markedly elevated islet-derived Reg2 and Reg3{beta}; administration of these proteins accelerated sympathetic regeneration and improved islet graft function. Our findings identify an islet-sympathetic architecture actively maintained by islets, uncovering an endocrine-driven mechanism for neural regulation, highlighting Reg2 and Reg3{beta} as therapeutic candidates for diabetes management.

neuroscience↗

bioRxiv2024

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs and CD8+ T cells

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effects in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages (TAMs), and citalopram treatment enhances local macrophage phagocytosis and elicits CD8+ T anti-tumor immunity. C5aR1 deficiency or depletion of CD8+ T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity, and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.

cancer biology↗

bioRxiv2024

SSRI antidepressant citalopram reverses the Warburg effect to inhibit hepatocellular carcinoma by directly targeting GLUT1

Although there is growing appreciation for effective repurposing of selective serotonin reuptake inhibitors (SSRIs) for cancer therapy, particularly hepatocellular carcinoma (HCC), efforts are hampered by limited knowledge of their molecular targets and mechanism of action. Global inverse gene-expression profiling method, drug affinity responsive target stability assay, and in silico molecular docking analysis was performed to identify the targets of SSRIs. Murine subcutaneous, orthotopic models, and patient-derived xenograft were employed to explore the therapeutic effects and underlying mechanisms of SSRIs in HCC. The clinical relevance of SSRI use was verified with real world data. SSRIs exhibit significant anti-HCC effects independent of their known target serotonin reuptake transporter. The glucose transporter 1 (GLUT1) is identified as a new target of SSRIs. Citalopram binds to and antagonizes GLUT1, resulting in reduced glycolytic flux and ATP generation. Mutant GLUT1 in the binding site E380 of citalopram compromises the inhibitory effects of citalopram on the Warburg effect and tumor growth. In preclinical models, citalopram dampens the growth kinetics of GLUT1high liver tumors and displays a synergistic effect with anti-PD-1 therapy. Retrospective analysis of health records found that SSRIs use is associated with a lower risk of metastasis among HCC patients. Our study reveals an unprecedented role of SSRIs in cancer metabolism, and establishes a rationale for repurposing SSRIs as potential anticancer drugs for HCC.

cancer biology↗

bioRxiv2024

Mechanical cues of extracellular matrix determines tumor innervation

Peripheral tumors can establish local autonomic and sensory nerve networks, termed as tumor innervation (TIN), to support tumorigenesis and metastasis. While nerve dependence in cancers is well-established, the mechanisms governing TIN remain unclear. Here, we report that extracellular matrix (ECM) stiffness, a major mechanical abnormality in the tumor microenvironment (TME), is an essential contributor of TIN. In preclinical models, reducing lysyl oxidase-mediated ECM crosslinking lowers tissue stiffness and TIN in pancreatic cancer, while inflammation-induced matrix stiffening boosts the hyperinnervation of the pancreatic precursor lesions. Mechanistically, {beta}1-containing integrins sense the mechanical cues exerted by ECM stiffness, and the translational co-activator YAP1 acts as an essential nuclear relay to induce the expression of neurotropic genes, particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). 3D imaging of the whole cleared pancreas reveals that blockade of mechanosensor integrin {beta}1 or pharmacological inhibition of the mechanotransducer YAP1 effectively reduces TIN. In clinical settings, tumor samples with a dense, crosslinked, and stiffened ECM exhibit significant TIN. In summary, these findings identify ECM stiffness as an important driver of TIN and suggest that targeting integrin {beta}1/YAP1-dependent mechanotransduction may counteract TIN.

neuroscience↗

bioRxiv2023

In silico MS/MS prediction for peptidoglycan profiling uncovers novel anti-inflammatory peptidoglycan fragments of the gut microbiota

Peptidoglycan is an essential exoskeletal polymer present across all bacteria. The gut microbiota-derived peptidoglycan fragments (PGNs) are increasingly recognized as key effector molecules that impact host biology, offering attractive yet untapped potential to combat microbiome-associated diseases in humans. Unfortunately, comprehensive peptidoglycan profiling of gut bacteria has been hampered by the lack of a robust and automated analysis workflow. Currently, PGN identification still relies on manual deconvolutions of acquired tandem mass spectrometry (MS/MS) data, which are highly laborious and inconsistent. Recognizing the unique sugar and amino acid makeup of bacterial peptidoglycan and guided by the experimental MS/MS fragmentation patterns of known PGNs, we developed a computational tool PGN_MS2 that reliably simulates MS/MS spectra of PGNs. Integrating PGN_MS2 into the customizable in silico PGN database, we built an open-access PGN MS library of predicted MS/MS spectra for all molecules in the user-defined in silico PGN search space. With this library, automated searching and spectral matching can be used to identify PGN. We then performed comprehensive peptidoglycan profiling for several gut bacteria species, revealing distinct PGN structural features that may be implicated in microbiota-host crosstalk. Strikingly, the probiotic Bifidobacterium spp. has an exceedingly high proportion of anhydro-PGNs, which exhibit anti-inflammatory effects in vitro. We further identified MltG and RfpB homologs in Bifidobacterium as lytic transglycosylases (LTs), which demonstrate distinct substrate preferences to produce anhydro-PGNs. Overall, our novel PGN_MS2 prediction tool contributes to the robust and automated peptidoglycan analysis workflow, advancing efforts to elucidate the structures and functions of gut microbiota-derived PGNs in the host.

microbiology↗

bioRxiv2021

An intein-split transactivator for intersectional neural imaging and optogenetic manipulation

The complexity of brain circuitry is manifested by numerous cell types based on genetic marker, location and neural connectivity. Cell-type specific recording and manipulation is essential to disentangle causal neural mechanisms in physiology and behavior; however, many current approaches are largely limited by number of intersectional features, incompatibility of common effectors and insufficient gene expression. To tackle these limitations, we devise an intein-based intersectional synthesis of transactivator (IBIST) to selectively control gene expression of common effectors in specific cell types defined by a combination of multiple features. We validate the specificity and sufficiency of IBIST to control common effectors including fluorophores, optogenetic opsins and Ca2+ indicators in various intersectional conditions in vivo. Using IBIST-based Ca2+ imaging, we show that the IBIST can intersect up to five features, and that hippocampal cells tune differently to distinct emotional valences depending on the pattern of projection targets. Collectively, the IBIST multiplexes the capability to intersect cell-type features and is compatible with common effectors to effectively control gene expression, monitor and manipulate neural activities.

neuroscience↗