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A vertical multico-culture system was established using human PDAC cells, neonatal mouse dorsal root ganglion neurons, and human pancreatic stellate cells. Migration and secretome proteomics indicated SPARC as a highly enriched factor in the DRG + PSC condition. Transcriptomic analyses linked SPARC upregulation to fibroblast predominance and worse survival, and immunohistochemistry in 81 resected specimens associated stromal-rich SPARC with PNI-positive status.",{"@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/sparc-is-associated-with-tumor-nerve-stroma-interactions-and-perineural-invasion-in-pancreatic-ductal-adenocarcinoma/361106/",{"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/sparc-is-associated-with-tumor-nerve-stroma-interactions-and-perineural-invasion-in-pancreatic-ductal-adenocarcinoma/361106.png","ImageObject",300,407,{"name":92,"@type":93},"kopisore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",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},"What experimental model was used to study perineural invasion in PDAC?","Question",{"text":112,"@type":113},"A vertical multico-culture model combined human PDAC cells, neonatal mouse dorsal root ganglion (DRG) neurons, and human pancreatic stellate cells (PSCs). Conditioned media were analyzed for protein changes and cell migration behavior.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How was SPARC identified as a factor related to tumor–nerve–stroma interactions?",{"text":117,"@type":113},"Proteomic profiling of conditioned media from the DRG + PSC co-culture revealed Secreted Protein Acidic and Rich in Cysteine (SPARC) as a highly enriched factor. Public transcriptomic datasets and protein-level analyses were used to validate its relevance.",{"name":119,"@type":110,"acceptedAnswer":120},"What clinical association was observed between SPARC and perineural invasion?",{"text":121,"@type":113},"Immunohistochemistry of 81 resected PDAC specimens showed that stromal-rich SPARC expression significantly correlated with PNI-positive status, indicating an association with PNI-related aggressiveness.","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},361106,1790192877,{"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":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":41},962090880963,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","[www. nature.com/scientificreports](www. nature.com/scientificreports)  \nOPEN  \nSPARC is associated with tumor nerve stroma interactions and perineural invasion in pancreatic ductal adenocarcinoma  \nSatoru Furuhashi1,2,7, Ryuta Muraki1,2,3,7, Yoshifumi Morita1􀀍, Daiki Nishiwaki1,  \nAkio Matsumoto1, Yuji Shimizu1, Tomohiro Murakami1, Makoto Takeda1, Hirotoshi Kikuchi1, Yoshihiro Hiramatsu1,4, Tomoaki Kahyo2, Mitsutoshi Setou2,5,6 & Hiroya Takeuchi1  \nPerineural invasion (PNI) is frequent in pancreatic ductal adenocarcinoma (PDAC) and contributes to poor prognosis, yet stromal–neural mechanisms remain unclear. We developed a vertical multico-culture model incorporating human PDAC cells, neonatal mouse dorsal root ganglion (DRG) neurons, and human pancreatic stellate cells (PSCs). Migration assays demonstrated markedly greater PDAC cell migration in DRG + PSC than either condition alone. Proteomic profiling of conditioned media identified Secreted Protein Acidic and Rich in Cysteine (SPARC) as a highly enriched factor inthe DRG + PSC condition. Public transcriptomic datasets (TCGA, GTEx, scRNA-seq) confirmed SPARC upregulation in PDAC, with predominant expression in fibroblasts and association with poor survival. Immunohistochemistry of 81 resected PDAC specimens in Hamamatsu University School of Medicine revealed stromal-rich SPARC expression significantly correlated with PNI-positive status. Collectively, these findings indicate that stromal SPARC is associated with PNI-related aggressiveness in PDAC. SPARC may serve as a biomarker of unfavorable prognosis and as a candidate stromal factor warranting future functional validation within the tumor-nerve-stromal axis.  \nKeywords Pancreatic ductal adenocarcinoma, Perineural invasion, Tumor microenvironment, Proteomics, SPARC  \nPancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a 5-year survival rate of approximately 10% globally, despite advances in diagnostic and therapeutic modalities1. The poor prognosis of PDAC is primarily due to the difficulty in early detection, frequent local invasion, and metastasis, making it often unresectable at the time of diagnosis. Additionally, PDAC is known for its high recurrence rate and resistance to chemotherapy2. Thus, improved recognition of the aggressive pathophysiology of PDAC is urgently warranted.  \nA distinctive feature of PDAC is its tendency for perineural invasion (PNI), with high frequency of 70.8% to 93% of surgical PDAC specimens3,4. The presence of PNI in PDAC is associated with local/distant recurrencesand can serve as an important prognostic factor5,6. PNI is increasingly recognized as the fourth mode of cancer invasion, following direct invasion, lymphatic invasion, and vascular invasion7. During PNI progression, the nerve sheath has been proposed as the path of least resistance for tumor spreading8. More recently, based on neurotropic theory, the nerves and invading tumor cells can interact with each other through neurotrophins9. However, the detailed molecular mechanisms of PNI development in PDAC remain unclear.  \n1Department of Surgery, Hamamatsu University School of Medicine, 1-20-1, Handayama, Chuou-ku, Hamamatsu 431-3125, Shizuoka, Japan. 2Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan. 3Department of Gastroenterological Surgery, Shizuoka General Hospital, Shizuoka, Shizuoka, Japan. 4Department of Perioperative Functioning Care and Support, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan. 5International Mass Imaging Center, Hamamatsu University School of Medicine, Hamamatsu, Japan. 6Department of Systems Molecular Anatomy, Institute for Medical Photonics Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan. 7Satoru Furuhashi and Ryuta Muraki contributed equally to this work. 􀀍 email: [yoshi-mo@hama-med.ac.jp](yoshi-mo@hama-med.ac.jp) ","cbCaicxIWTfFY32a","https://ap.wps.com/l/cbCaicxIWTfFY32a","pdf",2230226,12,"English","# Materials and methods\n## Study design and model development","[{\"question\":\"What experimental model was used to study perineural invasion in PDAC?\",\"answer\":\"A vertical multico-culture model combined human PDAC cells, neonatal mouse dorsal root ganglion (DRG) neurons, and human pancreatic stellate cells (PSCs). Conditioned media were analyzed for protein changes and cell migration behavior.\"},{\"question\":\"How was SPARC identified as a factor related to tumor–nerve–stroma interactions?\",\"answer\":\"Proteomic profiling of conditioned media from the DRG + PSC co-culture revealed Secreted Protein Acidic and Rich in Cysteine (SPARC) as a highly enriched factor. Public transcriptomic datasets and protein-level analyses were used to validate its relevance.\"},{\"question\":\"What clinical association was observed between SPARC and perineural invasion?\",\"answer\":\"Immunohistochemistry of 81 resected PDAC specimens showed that stromal-rich SPARC expression significantly correlated with PNI-positive status, indicating an association with PNI-related aggressiveness.\"}]","SPARC is associated with tumor nerve stroma interactions and perineural invasion in pancreatic ductal adenocarcinoma | PDF",1790143157]