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Xu et al. used human pancreas organoid–based CRISPR screens to uncover NF2 as a top tumor suppressor whose loss increases malignancy. NF2 inactivation promotes growth factor independence, boosts macropinocytosis under nutrient limitation, and drives YAP activation, enabling tumors to survive harsh microenvironment constraints.",{"@graph":69,"@context":123},[70,84,106],{"@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/merlins-disappearing-act-nf2-loss-conjures-pancreatic-cancer-survival-in-the-hostile-tumor-microenvironment-commentary/413771/",{"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/merlins-disappearing-act-nf2-loss-conjures-pancreatic-cancer-survival-in-the-hostile-tumor-microenvironment-commentary/413771.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What tumor microenvironment conditions shape pancreatic ductal adenocarcinoma survival?","Question",{"text":113,"@type":114},"PDAC cells face nutrient starvation, hypoxia, mechanical compression from stiff stroma, and dense stromal barriers, which together select for cells with mutations that improve fitness under stress.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How did Xu et al. identify NF2 in this study?",{"text":118,"@type":114},"They used human pancreas organoid–based CRISPR screens in a PDAC development model, where NF2-targeting sgRNAs were highly enriched across samples, indicating NF2 as a top tumor suppressor candidate.",{"name":120,"@type":111,"acceptedAnswer":121},"What are the key effects of NF2 loss on PDAC behavior?",{"text":122,"@type":114},"NF2 inactivation enhances PDAC malignancy, supports growth factor independence, increases macropinocytosis during nutrient deprivation, and triggers YAP activation that aligns with more aggressive, less differentiated tumor phenotypes.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},413771,1790818581,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":81,"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":39,"preview_page_count":4},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","The Journal of Clinical Investigation COMMENTARY  \nMerlin’s disappearing act: NF2 loss conjures pancreatic cancer survival in the hostile tumor microenvironment  \nSofia Ferreira1 and Laura D. Attardi1,2  \n1Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA. 2Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.  \nPancreatic cancer cells “live on the edge,” starved of nutrients, compressed by abundant stiff stroma, and deprived of oxygen. In this issue, Xu et al. leveraged human pancreas organoid–based CRISPR screens to identify new driver genes in pancreatic ductal adenocarcinoma (PDAC) development. Neurofibromatosis type 2 (NF2) emerged as the top tumor suppressor, whose loss enhances PDAC malignancy. Inactivation of NF2, which encodes the protein Merlin, promoted growth factor independence and enhanced macropinocytosis upon nutrient deprivation. Thus, NF2 status dictates the adaptability of pancreatic tumors under nutrient limitation, with NF2 inactivation endowing PDACs with the ability to survive the constraints of the harsh tumor microenvironment.  \nPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer deaths in the United States, with a 5-year survival rate of merely 13%(1, 2) . PDACis so deadly because it is often diagnosed at advanced stages, is largely unresponsive to existing therapies, and is associated with an aggressive, tumorpromoting microenvironment (3) . Specifically, hypoxia, nutrient scarcity, mechanical compression, and dense stroma conspire against cell survival, selecting for cells with mutations that confer enhanced fitness in this harsh microenvironment (3) . PDAC is driven by activating mutations in the KRAS oncogene, along with inactivating mutations in the TP53, CDKN2A, and SMAD4 tumor suppressor genes (4, 5) . While these tumor suppressors are frequently mutated in PDAC, there are numerous, less common genetic alterations observed in PDAC that might contribute to tumor development (4, 5) . Uncovering these underappreciated mutations is crucial both for understanding PDAC biology and for identifying new therapeutic vulnerabilities in this devastating disease.  \nPDAC can arise either from acinar cells, the cells of the pancreas that secrete digestive enzymes, or ductal cells, the cells that line the conduits that carry digestive enzymes (6, 7) . Notably, gene expression profiling has revealed that acinar cell– derived and ductal cell–derived PDACs in mice resemble the classical and basal-like subtypes of human PDAC (8) . In this issue, Xu et al. used an organoid model they developed to identify new players in acinar cell–derived PDAC (9) . In this model, termed KPT, they overexpressed KRASG12Vand inactivated both the CDKN2A/P16 and TP53 tumor suppressors in normal human pancreatic acinar cells and performed a pooled CRISPR-KO screen targeting 199 recurrently inactivated genes identified inpatients with PDAC.  \nNF2 inactivation unleashes an aggressive PDAC phenotype By performing CRISPR screens in an in vivo xenograft model, Xu et al. identified neurofibromatosis type 2 (NF2) as the top  \nRelated Article: [https://doi.org/10.1172/JCI194395](https://doi.org/10.1172/JCI194395)  \nConflict of interest: The authors have declared that no conflict of interest exists.  \nCopyright: © 2026, Ferreira et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.  \nReference information: J Clin Invest. 2026;136(1):e200909 . [https://doi.org/10.1172/JCI200909](https://doi.org/10.1172/JCI200909) .  \nhit, with sgRNAs targeting NF2 highly enriched in all samples (9) . NF2 encodes Merlin, a FERM domain protein that negatively regulates cell proliferation by serving as a linker between the plasma membrane and the actin cytoskeleton and modulating cell signaling (10) . NF2 has been primarily appreciated as a t","cbCaivwSHd4MjVR2","https://ap.wps.com/l/cbCaivwSHd4MjVR2","pdf",502379,"English","# Merlin’s disappearing act: NF2 loss in pancreatic cancer\n## CRISPR screens identify NF2 as a key tumor suppressor\n## NF2 inactivation enhances aggressiveness and survival\n## Metabolic rewiring and YAP/WNT7B signaling","[{\"question\":\"What tumor microenvironment conditions shape pancreatic ductal adenocarcinoma survival?\",\"answer\":\"PDAC cells face nutrient starvation, hypoxia, mechanical compression from stiff stroma, and dense stromal barriers, which together select for cells with mutations that improve fitness under stress.\"},{\"question\":\"How did Xu et al. identify NF2 in this study?\",\"answer\":\"They used human pancreas organoid–based CRISPR screens in a PDAC development model, where NF2-targeting sgRNAs were highly enriched across samples, indicating NF2 as a top tumor suppressor candidate.\"},{\"question\":\"What are the key effects of NF2 loss on PDAC behavior?\",\"answer\":\"NF2 inactivation enhances PDAC malignancy, supports growth factor independence, increases macropinocytosis during nutrient deprivation, and triggers YAP activation that aligns with more aggressive, less differentiated tumor phenotypes.\"}]","Merlin’s disappearing act: NF2 loss conjures pancreatic cancer survival in the hostile tumor microenvironment - Commentary | PDF",1790595730]