[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-374922-105":59,"doc-detail-374922-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","lack-of-caspase-8-directs-neuronal-progenitor-like-reprogramming-and-small-cell-lung-cancer-progression","Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression","","Most neuroendocrine cancers show little or no caspase 8 protein. The study builds a mouse model of small cell lung cancer that matches this caspase 8 deficiency and reveals a necroptosis-driven, pre-tumoral inflammatory program. This program reprograms tumor cells toward a neuronal progenitor-like state and accelerates metastatic progression. Caspase 8 loss increases recruitment of regulatory T cells, promoting metastasis, while MLKL inactivation reverses inflammation, reduces metastasis, and limits neuronal-like reprogramming.",{"@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/lack-of-caspase-8-directs-neuronal-progenitor-like-reprogramming-and-small-cell-lung-cancer-progression/374922/",{"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/lack-of-caspase-8-directs-neuronal-progenitor-like-reprogramming-and-small-cell-lung-cancer-progression/374922.png","ImageObject",300,407,{"name":92,"@type":93},"nayy☆","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main observation about caspase 8 in neuroendocrine cancers?","Question",{"text":112,"@type":113},"Most neuroendocrine cancers lack caspase 8 protein expression, and this study shows that caspase 8 loss has an unanticipated cancer-regulatory function.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does caspase 8 loss influence small cell lung cancer progression?",{"text":117,"@type":113},"Caspase 8 deficiency in the pre-tumoral niche promotes necroptosis-driven inflammation, drives reprogramming toward a neuronal progenitor-like state, and increases metastatic disease.",{"name":119,"@type":110,"acceptedAnswer":120},"What effect does blocking necroptosis executioner MLKL have?",{"text":121,"@type":113},"Inactivation of MLKL reverses pre-tumoral inflammation, decreases metastasis, and reduces neuronal-like reprogramming.","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},374922,1790252885,{"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":34,"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},962090893153,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","Article [https://doi.org/10.1038/s41467-025-67142-4](https://doi.org/10.1038/s41467-025-67142-4)  \nLack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression  \nReceived: 22 September 2025  \n\n| Accepted: 24 November 2025 |\n| --- |\n| |\n| Check for updates |\n\nAriadne Androulidaki1,2, Fanyu Liu1,2, Christina M. Bebber 1,2, Ilmars Kisis 1, Vignesh Sakthivelu 1, Pascal Hunold 3, Lioba Koerner 2,4,  \nAlina Dahlhaus 1,2, Fatma Isil Yapici 1,2, Christina Grimm 3,5,  \nAlicja Pacholewska 3,5, Sofya Tishina 1,2, Franka Doskotz 1,2,  \nLucia A. Torres Fernández 1, Jenny Stroh1,2, Ali T. Abdallah2,6,7, Julia Beck1,2, Lejla Mulalic1,2, Anna Schmitt2,8, Holger Grüll9, Thorsten Persigehl9, Alexander Quaas10, Martin Peifer 1,3, Johannes Brägelmann 1,3,11,  \nH. Christian Reinhardt 12, Pascal Nieper1,8, Robert Hänsel-Hertsch 3, Roman K. Thomas 1,10, Julie George 1,13, Michal R. Schweiger 3,5, Manolis Pasparakis 2,3,4, Filippo Beleggia 1,8,11 & Silvia von Karstedt 1,2,3   \nMost neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancerregulatory function has remained unexplored. Here, we devise a mouse model of small cell lung cancer (SCLC) recapitulating the lack of expression of caspase 8 seen in humans and uncover an unexpected role for necroptosis-fueled pre-tumoral inflammation resulting in reprogramming towards a neuronal progenitor cell-like state and increased metastatic disease. Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic humanSCLC. Mechanistically, caspase8loss within the pre-tumoral niche promotes inflammation marked by increased recruitment of regulatory T cells (Tregs) which are responsible for the promotion of metastatic disease. Importantly, inactivation of the necroptosis executioner MLKL reverses pretumoral inflammation, decreases metastasis as well as neuronal-like reprogramming. Taken together, our findings suggest that pre-tumoral inflammatory cell death contributes to neuronal progenitor mimicry, immunosuppression and increased metastasis in SCLC.  \nSmall cell lung cancer (SCLC) is amongst the most aggressive forms of lung cancer with a 5-year survival rate of only 5%1. Despite this dismal prognosis, SCLC is initially highly sensitive to chemotherapy in most cases, but patients inevitably relapse with very rapid progression. SCLC unlike other epithelial cancers is thought to arise from a distinct cellular population of pulmonary neuroendocrine cells (PNECs) which share features with neuronal cells2,3. Normal neural stem or progenitor cells were shown to lack caspase 8 expression4 suggesting this to be a  \ncharacteristic neuroendocrine (NE) feature. Indeed, lack of caspase-8 expression is frequently observed in other NE cancer entities, including neuroblastoma, medulloblastoma, and glioblastoma5. Human SCLC, but not non-small cell lung cancer (NSCLC) cell lines, lacked caspase 8 expression and, asa result ofthis, were resistant to induction of extrinsic apoptosis6. DNA hypermethylation within the caspase 8 gene promoter region was found in SCLC primary tumors and carcinoid tumor samples, indicating epigenetic rather than genetic loss7.  \nA full list of affiliations appears at the end of the paper. e-mail: [s.vonkarstedt@uni-koeln.de](s.vonkarstedt@uni-koeln.de)  \na b c d  \ne  \nCASP8_NM033356 (FPKM)  \nf  \n0 1 2 3 4 5 Sum Methylation (Reg. 4-8)  \nhNSCLC  \nhSCLCmNSCLCmSCLC  \n% of mice with tumor  \n150  \n100  \n50  \n0  \nj  \n metastasis  \n no metastasis p=0.0359  \nRP  \nRPC  \n% of total mice  \n150  \n100  \n50  \n0  \n dead  \nRP RPC  \nNCAM ASCL1 CD31 CD45  \nFig. 1 | Lack of caspase 8 expression promotes metastatic disease. a Caspase 8 protein expression (log2) of SCLC patients (n = 112) and matched adjacent normal lung samples (n = 112)18 is plotted. b Caspase 8 expression transcripts per kilobase million (TPM) (log2 TPM+1) in lung adenocarcinoma (TCGA; LUAD, n","cbCaijPcpdNSsH5N","https://ap.wps.com/l/cbCaijPcpdNSsH5N","pdf",3418766,17,"English","# Background and clinical relevance\n# Mouse model of small cell lung cancer with caspase 8 loss\n# Necroptosis-fueled pre-tumoral inflammation and neuronal-like reprogramming\n## Increased regulatory T cell recruitment\n# Mechanistic validation via MLKL inactivation\n# Biological and clinical implications for metastasis","[{\"question\":\"What is the main observation about caspase 8 in neuroendocrine cancers?\",\"answer\":\"Most neuroendocrine cancers lack caspase 8 protein expression, and this study shows that caspase 8 loss has an unanticipated cancer-regulatory function.\"},{\"question\":\"How does caspase 8 loss influence small cell lung cancer progression?\",\"answer\":\"Caspase 8 deficiency in the pre-tumoral niche promotes necroptosis-driven inflammation, drives reprogramming toward a neuronal progenitor-like state, and increases metastatic disease.\"},{\"question\":\"What effect does blocking necroptosis executioner MLKL have?\",\"answer\":\"Inactivation of MLKL reverses pre-tumoral inflammation, decreases metastasis, and reduces neuronal-like reprogramming.\"}]","Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression | PDF",1790202771,43]