Biology subjects

Hu, L.-P.

Publications and source records attributed to Hu, L.-P..

4 recordsLinked to original sources

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

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

A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer

BACKGROUND & AIMSPDAC is characterized by significant matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, it is not clear the connection between matrix stiffness and the Warburg effect and the mechanisms of action in tumor progression. METHODSThe relationship between matrix stiffness and the Warburg effect was investigated from clinical, cellular, and bioinformatical perspectives. The ChIP and luciferase reporter gene assays were used to clarify the regulation mechanism of matrix stiffness on the expression of CLIC1. The expression profile and clinical significance of CLIC1 were determined in GEO datasets and a TMA. Loss-of-function and gain-of-function technics were used to determine the in vitro and in vivo functions of CLIC1. GSEA and western blotting revealed the underlying molecular mechanisms. RESULTSPDAC matrix stiffness is closely associated with the Warburg effect, and CLIC1 is a key molecule connecting tumor matrix stiffness and the Warburg effect. Increased CLIC1 expression induced by matrix stiffness correlates with poor prognosis in PDAC. CLIC1 acts as a promoter of glycolytic metabolism and facilitates tumor growth in a glycolysis-dependent manner. Mechanistically, CLIC1 inhibits the hydroxylation of HIF1 via ROS, which then increases the stability of HIF1. Collectively, PDAC cells can sense extracellular matrix stiffness and upregulate the expression of CLIC1, which facilitates the Warburg effect through ROS/HIF1 signaling, thereby supporting tumor growth. CONCLUSIONSIn the context of tumor therapy, targeted approaches can be considered from the perspectives of both extracellular matrix stiffness and tumor metabolism, of which CLIC1 is one of the targets.

cancer biology↗