LIS1 mediated Schwann cell reprogramming enhances perineural invasion by activating the Serine/NMDAR/AKT signaling pathway in head and neck squamous carcinoma

LIS1 mediated Schwann cell reprogramming enhances perineural invasion by activating the Serine/NMDAR/AKT signaling pathway in head and neck squamous carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article LIS1 mediated Schwann cell reprogramming enhances perineural invasion by activating the Serine/NMDAR/AKT signaling pathway in head and neck squamous carcinoma Lu Gao, Jing Liu, Ao Dai, Yiding Liu, Yuying Zhang, Bing Yan, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6307106/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Perineural invasion (PNI) has significant implications for the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Lissencephaly-1 (LIS1) plays a crucial role in neural development and is highly expressed in HNSCC, showing a positive correlation with tumor invasion. However, the precise role of LIS1 in PNI and its underlying molecular mechanisms are not well understood. Here, we demonstrated that LIS1 expression was positively correlated with PNI and GFAP+ schwann cells (SCs). In vitro PNI model indicated HNSCC cells overexpressing LIS1 exhibited enhanced PNI capacity. Importantly, the microfluidic chip revealed that LIS1 in tumor cells stimulated the migration of SCs, resulting in increased levels of PNI-related factors, which in turn promoted the progression of PNI in HNSCC. Additionally, RNA sequencing analysis identified the regulatory effects of LIS1 on three enzymes of PHGDH, PSAT1, and PSPH, which enhanced the serine synthesis. The serine upregulated by LIS1 in tumor cells activated SCs through the NMDAR/AKT signaling pathway. Finally, in vivo experiments utilizing a mouse sciatic nerve invasion model provided further confirmation of these findings. Our study identifies LIS1 as a potential predictive marker for PNI and highlights its importance as a therapeutic target for the treatment of HNSCC. Biological sciences/Cancer/Cancer microenvironment Health sciences/Biomarkers/Prognostic markers HNSCC LIS1 Serine SCs PNI NMDAR Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Full Text Additional Declarations There is no conflict of interest Supplementary Files SupplementaryFiguresandFigureLegends.pdf Supplementary Figures and Figure Legends GraphicalAbstract.jpg Graphical Abstract Supplementarytablesandmethods.pdf Supplementary tables and methods Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6307106","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":451137456,"identity":"64ea55b4-e920-4fbd-b0f9-6e99561fdf6c","order_by":0,"name":"Lu Gao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYDCCA2DEIMPA3tj48AMpWngYeA43G0sQq4UBrEUivU2AhxgdfMfPGB78UmPDY3DzYRuDBIOdnG4DAS2SZ3IMDsscS+MxuJ3Y9qCAIdnY7AABLQYHgFok2A6DtLQbSDAcSNxGUMv5N0At/4Babh5sk+AhSsuNHIODH9uAWm4wEqlF8sazgsOMfWk8kmcSgYFsQIRf+M4nb/7445uNHN/x4w8ffqiwkyOohYGBw4AZER0GBJWDAPsDxh9EKRwFo2AUjIIRCwBLwUoW8/z7PwAAAABJRU5ErkJggg==","orcid":"","institution":"Dalian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Lu","middleName":"","lastName":"Gao","suffix":""},{"id":451137457,"identity":"7e09adb9-0ab7-4673-b26d-e3219dbdd4b5","order_by":1,"name":"Jing Liu","email":"","orcid":"","institution":"Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Liu","suffix":""},{"id":451137458,"identity":"7ff52157-c5e7-4212-99b1-5f92b88fa8cf","order_by":2,"name":"Ao Dai","email":"","orcid":"","institution":"Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ao","middleName":"","lastName":"Dai","suffix":""},{"id":451137459,"identity":"fb04cde0-cbd0-4f1b-9b30-9723a0804723","order_by":3,"name":"Yiding Liu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yiding","middleName":"","lastName":"Liu","suffix":""},{"id":451137460,"identity":"f45063d3-9d15-471f-8495-3bb38062493c","order_by":4,"name":"Yuying Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yuying","middleName":"","lastName":"Zhang","suffix":""},{"id":451137461,"identity":"f1ba69f7-81e6-444c-8199-cd9d5fb0738c","order_by":5,"name":"Bing Yan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Yan","suffix":""},{"id":451137462,"identity":"56843b31-0522-40ec-be3f-5c2ac1729e00","order_by":6,"name":"Dong Jin","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Dong","middleName":"","lastName":"Jin","suffix":""},{"id":451137463,"identity":"a71ce17b-50f3-4682-90b9-25e3532bc671","order_by":7,"name":"Fu Wang","email":"","orcid":"https://orcid.org/0000-0001-9615-1038","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Fu","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-03-25 23:10:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6307106/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6307106/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81965771,"identity":"433cdad0-7ed2-41f8-acec-1912ee6f5ad5","added_by":"auto","created_at":"2025-05-05 11:32:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4412864,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 high expression in HNSCC tissues and its correlation with PNI. A. Differential expression of LIS1 in HNSCC carcinomas and paracancerous tissues in the TIMER database. B. Differential expression of LIS1 in HNSCC carcinomas and paracancerous tissues in the GEPIA2 database. C. Representative images (20x and 10x) of LIS1, S100, and GFAP expression in PNI positive (+) and PNI negative (−) human HNSCC tissues. D. Statistical analysis of IHC staining for LIS1. E. Pearson correlation analysis of the mean density of LIS1 and S100, LIS1 and GFAP in human HNSCC tissues. F. Representative images (20x) of GDNF expression in LIS1 high and LIS1 low human HNSCC tissues. G. Pearson correlation analysis of the mean density of LIS1 and GDNF in human HNSCC tissues. Data are represented as mean ± SEM, **P\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Figures1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/537194c9d4dc12dc74a3a544.jpg"},{"id":81964527,"identity":"77ebee39-9038-4249-9a6b-16ef65c6dd3d","added_by":"auto","created_at":"2025-05-05 11:24:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3738133,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 increases the migration, invasion, and PNI capability of HNSCC cells. A. Wound healing assay of LIS1 overexpression or LIS1 knockdown in SCC25 cells. B. Transwell assay of LIS1 overexpression or LIS1 knockdown in SCC25 cells. C. Representative images of the in vitro PNI model for LIS1 overexpression or LIS1 knockdown in SCC25 cells. D. Microfluidic chip pattern diagram and representative images of LIS1 overexpression or LIS1 knockdown in SCC25 cells co-cultured with SCs in the microfluidic chip. Data are represented as mean ± SEM, * P\u0026lt;0.05, **P\u0026lt;0.01, *** P\u0026lt;0.001, **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figures2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/5797e66f9d915565ecd73d45.jpg"},{"id":81964521,"identity":"c9eb8354-b0b5-40bd-a628-fd0cba9bf91f","added_by":"auto","created_at":"2025-05-05 11:24:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2226147,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 overexpression of HNSCC cells increases Schwann cells activity. A. The pattern diagram of HNSCC cells co-cultured with SCs. B. Transwell assay of sNF96.2 cells co-cultured with SCC25 cells. C. The mRNA expression of PNI-related factors (BDNF, GDNF, NGF, MMP2, and MMP9) in sNF96.2 cells co-cultured with SCC25 cells were analyzed by RT-qPCR. D. IF double staining was performed to detect the expression of S100 and GFAP in the sNF96.2 cells co-cultured with SCC25 cells. Data are represented as mean ± SEM, * P\u0026lt;0.05, **P\u0026lt;0.01, *** P\u0026lt;0.001, **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figures3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/90aef10371190420b20e136b.jpg"},{"id":81964517,"identity":"1151fed2-7c7c-4ed4-b1e9-63e7fa745abd","added_by":"auto","created_at":"2025-05-05 11:24:50","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1814701,"visible":true,"origin":"","legend":"\u003cp\u003eTranscriptome sequencing reveals LIS1 activates the serine metabolic signaling pathway in HNSCC cells. A. The 2D PCA plot illustrating sample distribution along PC1 (41.77%) and PC2 (21.15%), with variance indicated; B. Volcano plot showing differential expression analysis, with log2 fold change (LogFC) on the x-axis and -log10 adjusted p-value on the y-axis; C. Bar chart displaying significant biological processes (BP), cellular components (CC), and molecular functions (MF) identified through GO enrichment analysis, with P-adjust values indicated; D. Summary of KEGG pathway enrichment results for glycine, serine, and threonine metabolism, and cytokine-cytokine receptor interaction; E. Heatmap representing normalized expression levels of various KEGG pathways with color gradient indicating pathway activity calculated using GSVA; F. Heatmap representing the expression levels of genes involved in the KEGG pathway for glycine, serine, and threonine metabolism across different samples.\u003c/p\u003e","description":"","filename":"Figures4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/2b1ab7ceec7c7d6cddbbd9bb.jpg"},{"id":81964530,"identity":"c36de3fa-ab66-48c9-a46c-c83020535edf","added_by":"auto","created_at":"2025-05-05 11:24:51","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":2735191,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 overexpression activates the serine signaling pathway to promote the PNI in HNSCC cells. A. The mRNA expression of PHGDH, PSAT1, and PSPH in SCC25 cells were analyzed by RT-qPCR. B. Analysis of the relative intracellular serine levels in SCC25 cells. C. The protein level of PHGDH, PSAT1, and PSPH in SCC25 cells were analyzed by WB. D. Migration and invasion assay of shLIS1 group after exogenous serine stimulation of SCC25 cells and quantitative analysis. E. Representative images of the in vitro PNI model for shLIS1 group after exogenous serine stimulation of SCC25 cells and the analysis of neural invasion index. F. Representative images of the microfluidic chip for shLIS1 group after exogenous serine stimulation of SCC25 cells and analysis of migration distance. Data are represented as mean± SEM, **P\u0026lt;0.01, *** P\u0026lt;0.001, **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figures5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/256fab014b44d24060b318cf.jpg"},{"id":81964522,"identity":"b985d01b-b643-4d1b-89bc-1a555c53097c","added_by":"auto","created_at":"2025-05-05 11:24:50","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":2869927,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 enhanced serine in HNSCC cells could activate the NMDAR/AKT signal of Schwann cells. A. The protein level of AKT and P-AKT (473) in sNF96.2 cells were analyzed by WB. B. The protein level of AKT and P-AKT (473) in sNF96.2 cells after MK801 (a NMDAR inhibitor) treatment by WB. C. Migration and invasion assay of sNF96.2 cells after MK801 or MK2206 (an AKT inhibitor) treatment. D. Representative images of the in vitro PNI model for LIS1 overexpression group after MK801 or MK2206 stimulation. E. IF double staining (S100 and GFAP) images (40x) showed that tumor-associated SCs were treated with MK801 or MK2206. F. The mRNA expression of BDNF, GDNF, NGF, MMP2, and MMP9 was detected in sNF96.2 cells after MK801 or MK2206 stimulation by RT719 qPCR. Data are represented as mean ± SEM, * P\u0026lt;0.05, **P\u0026lt;0.01, *** P\u0026lt;0.001, **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figures6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/fcfb22c64e65461f7a3b2c2c.jpg"},{"id":81965774,"identity":"1962ae5b-bd35-4311-b784-3623b43bc3e9","added_by":"auto","created_at":"2025-05-05 11:32:51","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":3929309,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 accelerated the PNI of HNSCC in vivo. A. Schematic of the PNI in vivo model. B. Representative images on hindlimb function of the mouse. C. Surgical images of the sciatic nerve PNI. D. Representative images (20x) of HE staining. E-G. Representative images (20x) of IHC staining for MMP2, Vimentin, and GDNF in mice tissues. H. IF double staining images (20x) of LIS1 and S100 in mice tissues and the Pearson correlation analysis of LIS1 and S100. Data are represented as mean ± SEM, * P\u0026lt;0.05, **P\u0026lt;0.01.\u003c/p\u003e","description":"","filename":"Figures7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/add1487181b8ec30fc046bdb.jpg"},{"id":81967541,"identity":"6eb1a696-5ec4-4b84-ac57-26db4eb97e76","added_by":"auto","created_at":"2025-05-05 11:40:50","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":3232686,"visible":true,"origin":"","legend":"\u003cp\u003eLIS1 promoted the PNI of HNSCC via serine/NMDAR/AKT axis in vivo. A. Representative images of IHC staining for PHGDH, NMDAR1, and P-AKT in mice tissues. B. The protein level of PHGDH, PSAT1, and PSPH in mice tissues were detected by WB. C. Expression of PHGDH, PSAT1, and PSPH in mice tissues were measured by RT-qPCR. D. IF double staining images (20x) of PHGDH and NMDAR in mice tissues and the Pearson correlation analysis of PHGDH and NMDAR. Data are represented as mean± SEM, * P\u0026lt;0.05, **P\u0026lt;0.01, *** P\u0026lt;0.001, **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"Figures8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/3e619b0f1c0ff6d8ea68610a.jpg"},{"id":83010261,"identity":"3ea73451-5e03-48cf-88a8-fc2ce1c669c3","added_by":"auto","created_at":"2025-05-19 04:43:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":25380045,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscrip0430.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1_covered_a37ef917-3cc0-4442-936a-1b1c47ecb817.pdf"},{"id":81964516,"identity":"328b90de-7d89-433f-87dd-ce0716d7a0fe","added_by":"auto","created_at":"2025-05-05 11:24:50","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":448693,"visible":true,"origin":"","legend":"Supplementary Figures and Figure Legends","description":"","filename":"SupplementaryFiguresandFigureLegends.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/cf2c7e70ceefc16d3b2a2936.pdf"},{"id":81965768,"identity":"94b4f328-f879-43d7-9200-3fd6742ed786","added_by":"auto","created_at":"2025-05-05 11:32:50","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":623339,"visible":true,"origin":"","legend":"Graphical Abstract","description":"","filename":"GraphicalAbstract.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/52ce36cc5e2533bebf014235.jpg"},{"id":81965769,"identity":"9f973c1d-923b-4ba5-8bf0-05d0b7f16c55","added_by":"auto","created_at":"2025-05-05 11:32:50","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":285358,"visible":true,"origin":"","legend":"Supplementary tables and methods","description":"","filename":"Supplementarytablesandmethods.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6307106/v1/10550394408c0f62e7662ed1.pdf"}],"financialInterests":"There is no conflict of interest","formattedTitle":"LIS1 mediated Schwann cell reprogramming enhances perineural invasion by activating the Serine/NMDAR/AKT signaling pathway in head and neck squamous carcinoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HNSCC, LIS1, Serine, SCs, PNI, NMDAR","lastPublishedDoi":"10.21203/rs.3.rs-6307106/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6307106/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Perineural invasion (PNI) has significant implications for the prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Lissencephaly-1 (LIS1) plays a crucial role in neural development and is highly expressed in HNSCC, showing a positive correlation with tumor invasion. However, the precise role of LIS1 in PNI and its underlying molecular mechanisms are not well understood. Here, we demonstrated that LIS1 expression was positively correlated with PNI and GFAP+ schwann cells (SCs). In vitro PNI model indicated HNSCC cells overexpressing LIS1 exhibited enhanced PNI capacity. Importantly, the microfluidic chip revealed that LIS1 in tumor cells stimulated the migration of SCs, resulting in increased levels of PNI-related factors, which in turn promoted the progression of PNI in HNSCC. Additionally, RNA sequencing analysis identified the regulatory effects of LIS1 on three enzymes of PHGDH, PSAT1, and PSPH, which enhanced the serine synthesis. The serine upregulated by LIS1 in tumor cells activated SCs through the NMDAR/AKT signaling pathway. Finally, in vivo experiments utilizing a mouse sciatic nerve invasion model provided further confirmation of these findings. Our study identifies LIS1 as a potential predictive marker for PNI and highlights its importance as a therapeutic target for the treatment of HNSCC.","manuscriptTitle":"LIS1 mediated Schwann cell reprogramming enhances perineural invasion by activating the Serine/NMDAR/AKT signaling pathway in head and neck squamous carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-05 11:24:45","doi":"10.21203/rs.3.rs-6307106/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"91aff9de-fae9-4d60-bed5-b8a16c1d0d45","owner":[],"postedDate":"May 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47998457,"name":"Biological sciences/Cancer/Cancer microenvironment"},{"id":47998458,"name":"Health sciences/Biomarkers/Prognostic markers"}],"tags":[],"updatedAt":"2025-05-19T04:35:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-05 11:24:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6307106","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6307106","identity":"rs-6307106","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}