[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-435659-105":59,"doc-detail-435659-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","spatial-confinement-of-the-areg-sox9-signaling-circuit-rethinking-tumor-stroma-interactions-in-gastric-cancer","Spatial confinement of the AREG - SOX9 signaling circuit - rethinking tumor - stroma interactions in gastric cancer","","Letter to the Editor proposing a spatially grounded framework for understanding drug resistance and tumor stemness in gastric cancer via the AREG–SOX9 signaling circuit. The authors critique correlation-based assumptions about iCAFs producing amphiregulin (AREG) through the AREG–ERBB2 axis and call for direct ligand–receptor spatial mapping to test causation. They recommend ex vivo slice assays with AREG neutralization ± trastuzumab, proximity ligation/phospho-mapping, and introduction of an interface signature linking AREG and SOX9 with immune exclusion and vascularity metrics.",{"@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/spatial-confinement-of-the-areg-sox9-signaling-circuit-rethinking-tumor-stroma-interactions-in-gastric-cancer/435659/",{"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/spatial-confinement-of-the-areg-sox9-signaling-circuit-rethinking-tumor-stroma-interactions-in-gastric-cancer/435659.png","ImageObject",300,407,{"name":92,"@type":93},"hdkawk","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What key limitation do the authors identify in the AREG–SOX9 model?","Question",{"text":112,"@type":113},"They note the mechanism is still theory because direct spatial mapping of ligand–receptor activity is missing, and correlation evidence can confuse proximity with causality.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What experiments do they suggest to test whether AREG-high iCAFs drive ERBB2-active clones and SOX9 induction?",{"text":117,"@type":113},"They propose ex vivo slice assays with AREG neutralization with or without trastuzumab, alongside in situ proximity ligation and phospho-mapping on defined interface zones.",{"name":119,"@type":110,"acceptedAnswer":120},"How does the letter propose improving therapeutic targeting of the stroma?",{"text":121,"@type":113},"It recommends “precision stromal targeting” by identifying and neutralizing the iCAF fraction that secretes AREG while preserving or leveraging restraining CAF capabilities, using single-cell spatial signatures and targeted delivery approaches.","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},435659,1791276527,{"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":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":14,"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":24,"preview_page_count":4},3985747859855,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Letter to the Editor  \nSpatial confinement of the AREG–SOX9 signaling circuit: rethinking tumor–stroma interactions in gastric cancer  \nAsra Amjad, MBBSa, Muhammad Talha Usman, MBBSb, Umair Ali, Pharm Dc, Raghabendra Kumar Mahato, MBBSd,*  \nTo the Editor,  \nWe continue to regard stomach tumors as uniform molecular entities while neglecting microanatomical signaling ecologies that genuinely cause resistance, which is a pressing issue that the manuscript highlights. To drive a transition from descriptive atlases to practical, spatially actionable research, this letter adopts a purposefully critical posture, not one that is hostile. The AREG–SOX9 axis is not just “interesting”; it is a perfect example of why many targeted medicines fall short: we have not figured out where the biology is focused. Through the AREG– ERBB2 axis, amphiregulin (AREG) produced by iCAFs is found to contribute to drug resistance and enhance tumor stemness by upregulating SOX9 expression in tumour cells[1] . Although this claim is based on correlation evidence that confuses proximity with causality, it is mechanistically reasonable. Spatial–functional corroboration is necessary for a genuinely critical perspective: are AREG-high iCAFs close to ERBB2-active clones? Does SOX9 induction decrease, and ERBB2 inhibitor sensitivity return when AREG is blocked in situ?  \nThe axis remains a theory rather than a clinically validated mechanism, given the absence of direct spatial mapping of ligand–receptor activity (e.g., phospho-ERBB2 colocalized with AREG sources) . We suggest using ex vivo slice assays with AREG neutralization ± trastuzumab and in situ proximity ligation/phospho-mapping on identified interface zones as an instantaneous, high-yield test to determine causation. The growth of bacteria-induced stomach cancer cells, elevated β -catenin levels, and development of stem cell-like characteristics all depended on SOX9 [2] . A compelling multi-hit concept  \naDepartment of Medicine, Islamic International Medical College, Riphah International University, Rawalpindi, Pakistan, bDepartment of Medicine, Gajju Khan Medical College, Swabi, Pakistan, cDepartment of Pharmacy, University of Swabi, Pakistan and dDepartment of Medicine,Gandaki Medical College Teaching Hospital and Research Center Pokhara, Nepal  \nSponsorships or competing interests that may be relevant to content are disclosed at the end of this article.  \n*Corresponding author. Address: Department of Medicine, Gandaki Medical College Teaching Hospital and Research Center, Pokhara 33700, Nepal. Tel.: +977-9745829807. E-mail: [102raghabendrakumarmahato@gmail.com](102raghabendrakumarmahato@gmail.com)[ ](102raghabendrakumarmahato@gmail.com)(R. K. Mahato).  \nCopyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. This isan open access article distributed under the terms of the Creative Commons AttributionNon Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Annals of Medicine & Surgery (2026) 88:1128–1129  \nReceived 21 November 2025; Accepted 25 November 2025  \nPublished online 12 December 2025  \n[http://dx.doi.org/10.1097/MS9.0000000000004538](http://dx.doi.org/10.1097/MS9.0000000000004538)  \n(microbiota→stroma→tumor) is introduced, citing bacteria asan upstream trigger of SOX9; however, geographical co-occurrence is often overlooked in the literature. Before we can make the case for a functional triad, it is imperative that we co-map microbial signatures with AREG-high iCAF niches at the microscopic level. If microbes are not accidental, new therapeutic ideas arise. For example, niche induction of SOX9 may be collapsed by spatially targeted microbiome modification (mucosal bacteriophage or localized antimicrobial methods) without causing systemic microbiome disruption, an idea that has not yet been investig","cbCaiaEf2YNqXdVK","https://ap.wps.com/l/cbCaiaEf2YNqXdVK","pdf",182684,"English","# Letter to the Editor\n## Rationale for spatially actionable research\n## Limits of correlation evidence and need for mapping\n## Proposed experimental approaches (slice assays, spatial proximity/phospho-mapping)\n## Precision stromal targeting and single-cell spatial signatures\n## Moving spatial technologies toward predictive assays","[{\"question\":\"What key limitation do the authors identify in the AREG–SOX9 model?\",\"answer\":\"They note the mechanism is still theory because direct spatial mapping of ligand–receptor activity is missing, and correlation evidence can confuse proximity with causality.\"},{\"question\":\"What experiments do they suggest to test whether AREG-high iCAFs drive ERBB2-active clones and SOX9 induction?\",\"answer\":\"They propose ex vivo slice assays with AREG neutralization with or without trastuzumab, alongside in situ proximity ligation and phospho-mapping on defined interface zones.\"},{\"question\":\"How does the letter propose improving therapeutic targeting of the stroma?\",\"answer\":\"It recommends “precision stromal targeting” by identifying and neutralizing the iCAF fraction that secretes AREG while preserving or leveraging restraining CAF capabilities, using single-cell spatial signatures and targeted delivery approaches.\"}]","Spatial confinement of the AREG - SOX9 signaling circuit - rethinking tumor - stroma interactions in gastric cancer | PDF",1790674661]