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To address this, the study generates human 3D heterocellular PDAC spheroids from cancer cells, endothelial cells, pancreatic stellate cells, and monocytes, and compares them with non-cancerous spheroids. Results show disrupted endothelial networks, monocyte/macrophage immunosuppressive markers, hypoxic cores, and cytokine shifts consistent with poor patient survival.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/characterization-of-3d-heterocellular-spheroids-of-pancreatic-ductal-adenocarcinoma-for-the-study-of-cell-interactions-in-the-tumor-immune-microenvironment/381362/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/characterization-of-3d-heterocellular-spheroids-of-pancreatic-ductal-adenocarcinoma-for-the-study-of-cell-interactions-in-the-tumor-immune-microenvironment/381362.png","ImageObject",300,407,{"name":92,"@type":93},"Sophia Brooks","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are existing PDAC preclinical models often insufficient for therapy development?","Question",{"text":112,"@type":113},"They fail to fully recapitulate the complex, heterogeneous tumor immune microenvironment (TIME) found in patients, limiting identification of clinically effective treatments.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What cell types are used to build the human 3D heterocellular PDAC spheroids?",{"text":117,"@type":113},"Cancer cells, endothelial cells, pancreatic stellate cells (PSC), and monocytes are combined to form the 3D heterocellular tumor spheroids.",{"name":119,"@type":110,"acceptedAnswer":120},"How do the tumor spheroids differ from non-cancerous spheroids in immune and microenvironment features?",{"text":121,"@type":113},"Tumor spheroids show a compromised endothelial network, monocyte/macrophage differentiation toward an immunosuppressive phenotype (e.g., CD163, CD206, PD-L1), a hypoxic core, and cytokine changes associated with poor survival and stronger immunosuppression.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},381362,1790298991,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":46,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":31},962084925636,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","TYPE Original Research PUBLISHED 14 July 2023  \nDOI 10.3389/fonc.2023.1156769  \nOPEN ACCESS  \nEDITED BY  \nManuela Viola,  \nUniversity of Insubria, Italy  \nREVIEWED BY Ting-Yuan Tu,  \nNational Cheng Kung University, Taiwan Rainer Heuchel,  \nKarolinska Instutet, CLINTEC, Sweden  \n*CORRESPONDENCE Giulio Giustarini  \n [Giulio_giustarini@immunol.a-star.edu.sg](Giulio_giustarini@immunol.a-star.edu.sg)[ ](Giulio_giustarini@immunol.a-star.edu.sg)Giulia Adriani  \n [Giulia_adriani@immunol.a-star.edu.sg](Giulia_adriani@immunol.a-star.edu.sg)  \nRECEIVED 01 February 2023  \nACCEPTED 27 June 2023  \nPUBLISHED 14 July 2023  \nCITATION  \nGiustarini G, Teng G, Pavesi A and Adriani G (2023) Characterization of 3Dheterocellular spheroids of pancreatic ductal adenocarcinoma for the study of cell interactions in the tumor immune microenvironment.  \nFront. Oncol. 13:1156769 .  \ndoi: 10.3389/fonc.2023.1156769  \nCOPYRIGHT  \n© 2023 Giustarini, Teng, Pavesi and Adriani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nCharacterization of 3Dheterocellular spheroids of pancreatic ductaladenocarcinoma for the study of cell interactions in the tumor immune microenvironment  \nGiulio Giustarini1*, Germaine Teng1, Andrea Pavesi 2,3 and Giulia Adriani 1,4*  \n1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore, 2 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore, 3 Mechanobiology Institute, National University of Singapore, Singapore, Singapore, 4 Department of Biomedical Engineering, National University of Singapore, Singapore, Singapore  \nPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies nowadays. The available chemo-and immunotherapies are often ineffective in treating PDAC due to its immunosuppressive and highly desmoplastic tumor immune microenvironment (TIME), which is hardly reproduced in the existing preclinical models. The PDAC TIME results from a peculiar spatial organization between different cell types. For this reason, developing new human models recapitulating the tissue organization and cell heterogeneity of PDAC is highly desirable. We developed human 3D heterocellular tumor spheroids of PDAC formed by cancer cells, endothelial cells, pancreatic stellate cells (PSC), and monocytes. As a control, we formed spheroids using immortalized epithelial pancreatic ductal cells (non-cancerous spheroids) with cellular heterogeneity similar to the tumor spheroids. Normal spheroids containing endothelial cells formed a complex 3D endothelial network significantly compromised in tumor spheroids. Monocyte/macrophages within the 4-culture tumor spheroids were characterized by a higher expression of CD163, CD206, PD-L1, and CD40 than those in the non-cancerous spheroids suggesting their differentiation towards an immunosuppressive phenotype. The heterocellular tumor spheroids presented a hypoxic core populated with PSC and monocytes/macrophages. The 4-culture tumor spheroids were characterized by spatial proximity of PSC and monocytes to the endothelial cells and a cytokine signature with increased concentrations of CXCL10, CCL2, and IL-6, which have been observed in PDAC patients and associated with poor survival. Further, 4-culture tumor spheroids decreased the concentrations of T-cell chemoattracting cytokines, i.e., CCL4, CCL5, and CXCL9, when compared with the non-cancerous spheroids, revealing a critical immunosuppressive feature of the different types of cells forming the tumor spheroids. Our results showed ","cbCaiqr2iMMoFijt","https://ap.wps.com/l/cbCaiqr2iMMoFijt","pdf",4801678,"English","# Introduction\n## Tumor immune microenvironment and therapy resistance\n## Rationale for 3D heterocellular spheroid models\n## Role of pancreatic stellate cells","[{\"question\":\"Why are existing PDAC preclinical models often insufficient for therapy development?\",\"answer\":\"They fail to fully recapitulate the complex, heterogeneous tumor immune microenvironment (TIME) found in patients, limiting identification of clinically effective treatments.\"},{\"question\":\"What cell types are used to build the human 3D heterocellular PDAC spheroids?\",\"answer\":\"Cancer cells, endothelial cells, pancreatic stellate cells (PSC), and monocytes are combined to form the 3D heterocellular tumor spheroids.\"},{\"question\":\"How do the tumor spheroids differ from non-cancerous spheroids in immune and microenvironment features?\",\"answer\":\"Tumor spheroids show a compromised endothelial network, monocyte/macrophage differentiation toward an immunosuppressive phenotype (e.g., CD163, CD206, PD-L1), a hypoxic core, and cytokine changes associated with poor survival and stronger immunosuppression.\"}]","Characterization of 3D Heterocellular Spheroids of Pancreatic Ductal Adenocarcinoma - for the Study of Cell Interactions in the Tumor Immune Microenvironment | PDF",1790245019]