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cells, macrophages, cancer, fig, cell, paad, gemcitabine, ccl, pubmed, model, tumor, google, scholar, expression, areg, pancreatic, pccs, analysis, macrophage, treatment, cas, data, coculture, days, loop, pathway, resistance, models, patients, study, central, development, mouse, pda, signaling, gene, infiltration, cscs, group, results, pdos, macrophagecclspareg, panc, clinical, feedback, stem, zhang, samples, high, vitro,

Topics {✒️}

macrophage-ccl5-sp1-areg loop played macrophage-ccl5-sp1-areg feedback loop ccr5/akt/sp1/cd44 pathway inhibitors ccr/akt/sp1/cd44 axis ccl-5/akt/sp1/cd44 axis macrophage-ccl5-sp1-areg loop single-cell rna-sequencing data single-cell rna-sequencing analysis ccr5/akt/sp1/cd44 axis ccl5/akt/sp1/cd44 axis 100 µl celltiter-glo® reagent ccl5/ccr5/sp1/cd44 axis ccr5/akt/sp1/cd44 pathway macrophage-derived ccl5 promotes single-cell rna- sequencing cancer stem/initiating cells macrophage k63-linked ubiquitination autophagy-related gene signature macrophage-derived ccl5 activates droplet-based microfluidic device ccl5/ccr5 axis contributes feedback loop enhances ccl5-ccr5 paracrine signaling ccr5/akt/sp1 pathway single-cell sequencing data ccl3–ccr5 axis contributes half-maximal inhibitory concentration sp1 chip-seq analysis erk-sp1-osmr pathway ccl5/sp1/cd44 axis autophagy-related immune targets biotin-conjugated anti-cytokines macrophage-related gemcitabine resistance modulating sp1/nanog signaling kaplan‒meier survival analysis kaplan–meier survival analysis droplet-based microfluidic plate macrophage-secreted ccl5 triggered positive feedback loop henan provincial people showed macrophage-induced gr 0 mg/ml collagenase type laboratory animal center mouse tumor-bearing models macrophage-derived ccl5 plays health science center gr-related genes ercc1 hippo-yap signaling pathway key signaling factors gemcitabine-related genes ercc1a

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• Why 90% of clinical drug development fails and how to improve it?

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         headline:Macrophage-organoid co-culture model for identifying treatment strategies against macrophage-related gemcitabine resistance
         description:Gemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes. To investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma. The macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data. Our study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.
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            Macrophages
            Cancer stem cells
            Cancer Research
            Immunology
            Apoptosis
            Oncology
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      headline:Macrophage-organoid co-culture model for identifying treatment strategies against macrophage-related gemcitabine resistance
      description:Gemcitabine resistance (GR) is a significant clinical challenge in pancreatic adenocarcinoma (PAAD) treatment. Macrophages in the tumor immune-microenvironment are closely related to GR. Uncovering the macrophage-induced GR mechanism could help devise a novel strategy to improve gemcitabine treatment outcomes in PAAD. Therefore, preclinical models accurately replicating patient tumor properties are essential for cancer research and drug development. Patient-derived organoids (PDOs) represent a promising in vitro model for investigating tumor targets, accelerating drug development, and enabling personalized treatment strategies to improve patient outcomes. To investigate the effects of macrophage stimulation on GR, co-cultures were set up using PDOs from three PAAD patients with macrophages. To identify signaling factors between macrophages and pancreatic cancer cells (PCCs), a 97-target cytokine array and the TCGA-GTEx database were utilized. The analysis revealed CCL5 and AREG as potential candidates. The role of CCL5 in inducing GR was further investigated using clinical data and tumor sections obtained from 48 PAAD patients over three years, inhibitors, and short hairpin RNA (shRNA). Furthermore, single-cell sequencing data from the GEO database were analyzed to explore the crosstalk between PCCs and macrophages. To overcome GR, inhibitors targeting the macrophage-CCL5-Sp1-AREG feedback loop were evaluated in cell lines, PDOs, and orthotopic mouse models of pancreatic carcinoma. The macrophage-CCL5-Sp1-AREG feedback loop between macrophages and PCCs is responsible for GR. Macrophage-derived CCL5 activates the CCR5/AKT/Sp1/CD44 axis to confer stemness and chemoresistance to PCCs. PCC-derived AREG promotes CCL5 secretion in macrophages through the Hippo-YAP pathway. By targeting the feedback loop, mithramycin improves the outcome of gemcitabine treatment in PAAD. The results from the PDO model were corroborated with cell lines, mouse models, and clinical data. Our study highlights that the PDO model is a superior choice for preclinical research and precision medicine. The macrophage-CCL5-Sp1-AREG feedback loop confers stemness to PCCs to facilitate gemcitabine resistance by activating the CCR5/AKT/SP1/CD44 pathway. The combination of gemcitabine and mithramycin shows potential as a therapeutic strategy for treating PAAD in cell lines, PDOs, and mouse models.
      datePublished:2023-08-09T00:00:00Z
      dateModified:2023-08-09T00:00:00Z
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         Gemcitabine resistance
         Organoids
         Macrophages
         Cancer stem cells
         Cancer Research
         Immunology
         Apoptosis
         Oncology
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         name:Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, China
         type:PostalAddress
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      address:
         name:Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, China
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      name:Shenzhen University
      address:
         name:School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
         type:PostalAddress
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      address:
         name:Department of Epidemiology, Dalian Medical University, Dalian, China
         type:PostalAddress
      name:Shenzhen University General Hospital, Shenzhen University
      address:
         name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
         type:PostalAddress
      name:Shenzhen University General Hospital, Shenzhen University
      address:
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         type:PostalAddress
      name:Shenzhen University Health Science Center
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Person:
      name:Shengwei Jiang
      affiliation:
            name:Shenzhen University General Hospital, Shenzhen University
            address:
               name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
            name:Shenzhen University Medical School
            address:
               name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
               type:PostalAddress
            type:Organization
      name:Tingwei Deng
      affiliation:
            name:Shenzhen University General Hospital, Shenzhen University
            address:
               name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
            name:Shenzhen University
            address:
               name:School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
      name:Huan Cheng
      affiliation:
            name:Dalian Medical University
            address:
               name:Department of Epidemiology, Dalian Medical University, Dalian, China
               type:PostalAddress
            type:Organization
      name:Weihan Liu
      affiliation:
            name:Dalian Medical University
            address:
               name:Department of Epidemiology, Dalian Medical University, Dalian, China
               type:PostalAddress
            type:Organization
      name:Dan Shi
      affiliation:
            name:Shenzhen University General Hospital, Shenzhen University
            address:
               name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
            name:Shenzhen University Medical School
            address:
               name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
               type:PostalAddress
            type:Organization
      name:Jiahui Yuan
      affiliation:
            name:Shenzhen University General Hospital, Shenzhen University
            address:
               name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
            name:Shenzhen University Medical School
            address:
               name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
               type:PostalAddress
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      name:Zhiwei He
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            name:Shenzhen University Medical School
            address:
               name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
               type:PostalAddress
            type:Organization
      name:Weiwei Wang
      affiliation:
            name:Henan Provincial People’s Hospital
            address:
               name:Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, China
               type:PostalAddress
            type:Organization
      name:Boning Chen
      affiliation:
            name:Henan Provincial People’s Hospital
            address:
               name:Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, China
               type:PostalAddress
            type:Organization
      name:Li Ma
      affiliation:
            name:Shenzhen University
            address:
               name:School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
            name:Dalian Medical University
            address:
               name:Department of Epidemiology, Dalian Medical University, Dalian, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Xianbin Zhang
      affiliation:
            name:Shenzhen University General Hospital, Shenzhen University
            address:
               name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Peng Gong
      affiliation:
            name:Shenzhen University General Hospital, Shenzhen University
            address:
               name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
               type:PostalAddress
            type:Organization
            name:Shenzhen University Health Science Center
            address:
               name:Carson International Cancer Center & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Health Science Center, Shenzhen, China
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
      name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
      name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
      name:School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
      name:Department of Epidemiology, Dalian Medical University, Dalian, China
      name:Department of Epidemiology, Dalian Medical University, Dalian, China
      name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
      name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
      name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
      name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
      name:Guangdong Provincial Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, China
      name:Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, China
      name:Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou, China
      name:School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen, China
      name:Department of Epidemiology, Dalian Medical University, Dalian, China
      name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
      name:Department of General Surgery & Institute of Precision Diagnosis and Treatment of Digestive System Tumors, Carson International Cancer Center, Shenzhen University General Hospital, Shenzhen University, Shenzhen, China
      name:Carson International Cancer Center & Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Health Science Center, Shenzhen, China

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