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Using single-cell and bulk RNA-seq bioinformatics, the study links SPP1+ TAM abundance with prognosis, identifies SPP1-associated key genes via weighted gene co-expression network analysis, and builds a Random Forest prognostic model.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/p4ha1-facilitates-spp1-tumor-associated-macrophages-by-activating-the-hypoxia-pathway-in-head-and-neck-squamous-cell-carcinoma/441312/",{"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/p4ha1-facilitates-spp1-tumor-associated-macrophages-by-activating-the-hypoxia-pathway-in-head-and-neck-squamous-cell-carcinoma/441312.png","ImageObject",300,407,{"name":92,"@type":93},"Mia  ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-03","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the study’s main question about SPP1+ TAMs in HNSCC?","Question",{"text":112,"@type":113},"The study investigates how SPP1+ tumor-associated macrophages are regulated in head and neck squamous cell carcinoma and how this relates to patient prognosis and diagnosis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does the research identify key genes related to SPP1+ macrophages?",{"text":117,"@type":113},"It uses single-cell and bulk RNA sequencing bioinformatics, including weighted gene co-expression network analysis, to pinpoint genes linked to SPP1+ macrophages and prognosis.",{"name":119,"@type":110,"acceptedAnswer":120},"What experimental evidence supports the role of P4HA1 and hypoxia signaling?",{"text":121,"@type":113},"In vitro assays show that knocking down P4HA1 lowers SPP1 expression in TAMs educated by HNSCC cells, while gene set analyses indicate P4HA1 mediates hypoxia pathways; xenograft models further confirm reduced malignant progression after P4HA1 knockdown.","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},441312,1790740278,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"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":145},687207024478,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","[www. nature.com/scientificreports](www. nature.com/scientificreports)  \nOPEN  \nP4HA1 facilitates SPP1+ tumorassociated macrophages by activating the hypoxia pathway in head and neck squamous cell carcinoma  \nYiding Liu1,2,5, Bing Yan1,2,5, Hui Dong4,5, Yi Li1,2, Yuying Zhang1,2, Yi Wang1,2, Ni Kou1,3􀀍 & Lu Gao1,2􀀍  \nTumor-associated macrophages (TAMs) with highly expressed secreted phosphoprotein 1 (SPP1) carry immunosuppressive property as a potential target for tumor metastasis. However, the mechanisms regulating SPP1 +TAMs in head and neck squamous cell carcinoma (HNSCC) remain poorly understood. This study employs a combination of single-cell and bulk RNA sequencing bioinformatics analysis to confirm the impact ofTAMs with high levels of SPP1 on patient prognosis. Additionally, Key genes linked to SPP1 + macrophages were identified using weighted gene co-expression network analysis. A prognostic model was built using the Random Forest algorithm. Here we show, P4HA1 is strongly correlated with SPP1 + macrophages and holds significant value in predicting patient prognosis and diagnosis. In vitro experiments demonstrated thatTAMs educated by HNSCC cells with knockdown P4HA1 expressed lower SPP1 level compared to the control group. Furthermore, Gene Set Variation Analysis and Gene Set Enrichment Analysis indicated that P4HA1 mediates the hypoxia pathway in  \nHNSCC. In xenografts model, P4HA1 knockdown effectively suppressed tumor malignant progress, confirming that P4HA1 was positive correlation with SPP1 +TAMs and could mediate tumor hypoxia pathways. Overall, this study identified P4HA1 as a key gene involved in regulating SPP1 +TAMs through modulating hypoxia, providing a potential macrophage-centered therapeutic target in HNSCC.  \nKeywords Tumor-associated macrophages, SPP1, P4HA1, Hypoxia, HIF-1α, HNSCC  \nAbbreviations  \nAUC Cocl2 GEO  \nGSEA  \nGSVA  \nHNCHIF-1α P4HA1 PLS-GLMPCA  \nPDXs  \nROS  \nArea under the curve Cobalt chloride 2  \nGene expression omnibus  \nGene set enrichment analysis  \nGene set variation analysis Head and neck cancers Hypoxia-inducible factor 1 alpha  \nProlyl 4-hydroxylase subunit alpha 1 Partial least squares generalized linear models Principal component analysis  \nPatient-derived xenografts Reactive oxygen species  \n1School of Stomatology, Dalian Medical University, No. 9 West Section, Lvshun South Road, Dalian 116044, P. R. China. 2Technology Innovation Center of Immune and Oral Development & Regeneration, Dalian Medical University, Dalian 116044, China. 3School of Stomatology, The Affiliated Stomatological Hospital of Dalian Medical University, Dalian 116027, China. 4Department of Stomatology, Second Affiliated Hospital of Dalian Medical University, Dalian 116011, China. 5Yiding Liu, BingYan and Hui Dong contributed equally to this work. 􀀍 email: [kouni1984@163.com](kouni1984@163.com); [dygaolu@dmu.edu.cn](dygaolu@dmu.edu.cn)  \n[www. nature.com/scientificreports/](www. nature.com/scientificreports/)  \nSVM  \nSPP1  \nSGLM  \nTAMs  \nTME  \nTCGA  \nUMAP WGCNAPHDs  \nα-KG  \nCA9  \nCM  \nROC  \nSupport vector machine Secreted phosphoprotein 1  \nStepwise generalized linear model Tumor-associated macrophages Tumor microenvironment The cancer genome atlas  \nUniform manifold approximation and projection algorithm Weighted gene co-expression network analysis  \nOxygen-dependent dioxygenases  \nAlpha-ketoglutarate Carbonic anhydrase 9  \nConfusion matrices  \nReceiver operating characteristic curve  \nHead and neck squamous cell carcinoma (HNSCC) accounts for approximately 90% of head and neck cancers (HNC) and is recognized as the sixth most common type of cancer worldwide1,2. Despite multidisciplinary treatment of locally advanced HNSCC by surgery combined with adjuvant chemoradiation or platinumbased concurrent chemoradiation, less than 50% of patients can be cured3. HNSCC is characterized by the heterogeneity of tumor tissues and the complexity of tumor microenvironment (TME)4. Tumor-associated macrophages (TAMs), the ","cbCaiosyC37it8vy","https://ap.wps.com/l/cbCaiosyC37it8vy","pdf",3990844,17,"English","# Background\n## TAMs and tumor microenvironment in HNSCC\n## SPP1 and hypoxia-associated macrophage roles\n# Methods Overview\n## Single-cell and bulk RNA-seq bioinformatics\n## WGCNA and prognostic modeling","[{\"question\":\"What is the study’s main question about SPP1+ TAMs in HNSCC?\",\"answer\":\"The study investigates how SPP1+ tumor-associated macrophages are regulated in head and neck squamous cell carcinoma and how this relates to patient prognosis and diagnosis.\"},{\"question\":\"How does the research identify key genes related to SPP1+ macrophages?\",\"answer\":\"It uses single-cell and bulk RNA sequencing bioinformatics, including weighted gene co-expression network analysis, to pinpoint genes linked to SPP1+ macrophages and prognosis.\"},{\"question\":\"What experimental evidence supports the role of P4HA1 and hypoxia signaling?\",\"answer\":\"In vitro assays show that knocking down P4HA1 lowers SPP1 expression in TAMs educated by HNSCC cells, while gene set analyses indicate P4HA1 mediates hypoxia pathways; xenograft models further confirm reduced malignant progression after P4HA1 knockdown.\"}]","P4HA1 facilitates SPP1+ tumor-associated macrophages by activating the hypoxia pathway in head and neck squamous cell carcinoma | PDF",1790695568,43]