IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2

IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2 | 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 IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2 Jeremy Rich, Po Zhang, Weichi Wu, Tengfei Huang, Xujia Wu, Donghai Wang, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6009404/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Drivers of therapeutic resistance in cancer include evolving tumor cell heterogeneity and the tumor microenvironment (TME). Here, we found that increased matrix stiffness promotes radioresistance in glioblastoma (GBM) and maintains tumor cell hierarchies. Differential gene expression revealed that stiff matrices induced expression of IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) through YAP1 and TEAD transcription factors in GBM stem cells (GSCs). IQGAP3 promoted GSC self-renewal and survival upon radiation treatment through binding and stabilization of core stem cell transcription factor, SOX2. Targeting IQGAP3 reduced SOX2 protein levels in vitro and in vivo, increasing GSC radiosensitivity and inhibiting tumor growth. Structure-function drug screening of FDA-approved agents blocking IQGAP3-SOX2 binding identified trimetrexate as a brain penetrant pharmacologic disruptor of IQGAP3 function in radioresistance, sensitizing GSCs to radiotherapy. These results identify molecular underpinnings for biomechanical promotion of cancer stem cell maintenance and therapeutic resistance, informing therapeutic strategies to augment efficacy of radiotherapy. Biological sciences/Cancer/CNS cancer Biological sciences/Cancer/Cancer stem cells glioblastoma matrix stiffness radiation IQGAP3 SOX2 cancer stem cell glioma stem cell Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplymentaryFig.pdf Supplymentary Figures SupplementaryTable9.xlsx Supplementary Table 9 SupplementaryTable12.xlsx Supplementary Table 12 SupplementaryTable6.xlsx Supplementary Table 6 SupplementaryTable8.xlsx Supplementary Table 8 SupplementaryTable13.xlsx Supplementary Table 13 SupplementaryTable10.xlsx Supplementary Table 10 SupplementaryTable2.xlsx Supplementary Table 2 SupplementaryTable7.xlsx Supplementary Table 7 SupplementaryTable1.xlsx Supplementary Table 1 SupplementaryTable14.xlsx Supplementary Table 14 nrreportingsummary.pdf Reporting summary SupplementaryTable3.xlsx Supplementary Table 3 SupplementaryTable4.xlsx Supplementary Table 4 SupplementaryTable11.xlsx Supplementary Table 11 SupplementaryTable5.xlsx Supplementary Table 5 rsnew.pdf Reporting summary sourcedata1.zip Supp Data ZIP Cite Share Download PDF Status: Under Review 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6009404","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":609563964,"identity":"41b3ded7-1e73-4a74-83fe-ce71910fd1c3","order_by":0,"name":"Jeremy Rich","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYDCCAwwJEAYzAxvDByDNxk6KFsYZIC3MhLXAARszD0QvfsB3+8DDxxUV2xK3tzM/e2zza5s8HzMD44ePObi1SJ5LSDY8c+Z24pzDbObGuX23DduYGZglZ27DrcXgDEOaZGPb7cQZzDxs0rk9txmBWtiYefFrSf/Z+A+qxbLntj0xWtIYGxugWhh+3E4kqEXyDEOyZMOx28YzmNnMJHsbbie3MTM24/UL3xmexI8NNbdlZ/Affibx489t2/ntzQc/fMSjhYGBJwFEOjaASMY2MNmATz0QsB8AkfYQzh8CikfBKBgFo2BEAgCCyVEcSSyXFQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7845-5302","institution":"UNC Lineberger Comprehensive Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Jeremy","middleName":"","lastName":"Rich","suffix":""},{"id":609563965,"identity":"c87719a0-1ede-484a-a69e-191f3fd7a9de","order_by":1,"name":"Po Zhang","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Po","middleName":"","lastName":"Zhang","suffix":""},{"id":609563966,"identity":"e21bb281-d1ca-49f9-9d3f-391575b02517","order_by":2,"name":"Weichi Wu","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Weichi","middleName":"","lastName":"Wu","suffix":""},{"id":609563967,"identity":"1ba041f8-c6e6-4de7-b254-f7dad6e6208e","order_by":3,"name":"Tengfei Huang","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Tengfei","middleName":"","lastName":"Huang","suffix":""},{"id":609563968,"identity":"98180495-02b5-4be9-89ca-b3b30c6df76f","order_by":4,"name":"Xujia Wu","email":"","orcid":"https://orcid.org/0000-0002-6904-0778","institution":"The First Affiliated Hospital, Sun Yat-sen University (FAH-SYSU)","correspondingAuthor":false,"prefix":"","firstName":"Xujia","middleName":"","lastName":"Wu","suffix":""},{"id":609563969,"identity":"b6fc1eac-7b6b-4e11-b8b4-eb9e0dfa4d69","order_by":5,"name":"Donghai Wang","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Donghai","middleName":"","lastName":"Wang","suffix":""},{"id":609563970,"identity":"dedb496b-20c0-4fc7-a4a2-cb3dc3da44ac","order_by":6,"name":"Huairui Yuan","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Huairui","middleName":"","lastName":"Yuan","suffix":""},{"id":609563971,"identity":"cf47412c-f45f-4e1c-b3c5-37e648ce7d4b","order_by":7,"name":"Suchet Taori","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Suchet","middleName":"","lastName":"Taori","suffix":""},{"id":609563972,"identity":"29ae4896-9e62-49c7-9437-f72dfaca6015","order_by":8,"name":"Fanen Yuan","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Fanen","middleName":"","lastName":"Yuan","suffix":""},{"id":609563973,"identity":"e4465ccd-a01c-4d6e-a7a1-fd8b27e49c30","order_by":9,"name":"Frank Vendetti","email":"","orcid":"","institution":"Hillman Cancer Center, UPMC, University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Frank","middleName":"","lastName":"Vendetti","suffix":""},{"id":609563974,"identity":"61c33bb2-5886-4a72-baac-81c812b8805c","order_by":10,"name":"Rui Wang","email":"","orcid":"","institution":"Hillman Cancer Center, UPMC, University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Wang","suffix":""},{"id":609563975,"identity":"ae58e5ea-7049-4e00-a140-a0da93a0f03f","order_by":11,"name":"Tingting Duan","email":"","orcid":"https://orcid.org/0000-0002-4482-5587","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Duan","suffix":""},{"id":609563976,"identity":"a8ae8bbd-605e-42ac-819e-18258a00daf9","order_by":12,"name":"Hailong Mi","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Hailong","middleName":"","lastName":"Mi","suffix":""},{"id":609563977,"identity":"0f4be541-9a44-4c3f-a593-3db602674149","order_by":13,"name":"Huan Li","email":"","orcid":"","institution":"Hillman Cancer Center, UPMC, University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Huan","middleName":"","lastName":"Li","suffix":""},{"id":609563978,"identity":"c8ecdabe-ddd0-4a84-a202-7441a43342ce","order_by":14,"name":"Kailin Yang","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Kailin","middleName":"","lastName":"Yang","suffix":""},{"id":609563979,"identity":"60f68fb6-cb11-4c51-a695-8ed308fcb293","order_by":15,"name":"Daqi Li","email":"","orcid":"https://orcid.org/0000-0002-7448-7435","institution":"Lineberger Comprehensive Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Daqi","middleName":"","lastName":"Li","suffix":""},{"id":609563980,"identity":"0c09b0e7-9c54-4afa-a6d4-f85e332272fe","order_by":16,"name":"Ahmed Habib","email":"","orcid":"","institution":"Hillman Cancer Center, UPMC, University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Ahmed","middleName":"","lastName":"Habib","suffix":""},{"id":609563981,"identity":"14ddf853-a5b7-4649-8849-c07c42c83e7b","order_by":17,"name":"Briana Prager","email":"","orcid":"","institution":"University of California, San Diego","correspondingAuthor":false,"prefix":"","firstName":"Briana","middleName":"","lastName":"Prager","suffix":""},{"id":609563982,"identity":"93a1d13e-10ec-43ce-befd-5c2da4ee712a","order_by":18,"name":"Ryan Gimple","email":"","orcid":"https://orcid.org/0000-0002-7189-3243","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Ryan","middleName":"","lastName":"Gimple","suffix":""},{"id":609563983,"identity":"62168e8e-e5d3-4d9e-988f-7183f277bbb5","order_by":19,"name":"Pascal Zinn","email":"","orcid":"","institution":"University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Pascal","middleName":"","lastName":"Zinn","suffix":""},{"id":609563984,"identity":"4943f748-b70b-4e83-a833-dd74e7a5ec6c","order_by":20,"name":"Kalil Abdullah","email":"","orcid":"","institution":"Hillman Cancer Center, UPMC, University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Kalil","middleName":"","lastName":"Abdullah","suffix":""},{"id":609563985,"identity":"652b1031-b568-46cb-bfdb-76a96affde18","order_by":21,"name":"Christopher Bakkenist","email":"","orcid":"","institution":"Hillman Cancer Center, UPMC, University of Pittsburgh","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Bakkenist","suffix":""},{"id":609563986,"identity":"5423075b-7924-4160-8f18-4cc309cc34d8","order_by":22,"name":"Junran Zhang","email":"","orcid":"https://orcid.org/0000-0001-5413-3675","institution":"Ohio State University","correspondingAuthor":false,"prefix":"","firstName":"Junran","middleName":"","lastName":"Zhang","suffix":""},{"id":609563987,"identity":"b66f5c4e-0ace-4ea1-8bf0-4040c88f2939","order_by":23,"name":"Qiulian Wu","email":"","orcid":"","institution":"UNC Chapel Hill US","correspondingAuthor":false,"prefix":"","firstName":"Qiulian","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2025-02-11 17:15:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6009404/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6009404/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106959526,"identity":"6dc4f097-ebf1-4f92-8644-eb0ed5648138","added_by":"auto","created_at":"2026-04-15 09:11:02","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":25515177,"visible":true,"origin":"","legend":"Article File","description":"","filename":"IQGAP3manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1_covered_f446bcf9-e566-4b8b-8f9b-120f92cda3f8.pdf"},{"id":106403057,"identity":"bfdfa414-323c-4c8e-9d26-97a61da598b9","added_by":"auto","created_at":"2026-04-08 09:13:29","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24593686,"visible":true,"origin":"","legend":"Supplymentary Figures","description":"","filename":"SupplymentaryFig.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/4b09c3e6e4349caa651dd63d.pdf"},{"id":106200397,"identity":"314df464-4e67-4442-8e64-87417b9f0a7e","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":131856,"visible":true,"origin":"","legend":"Supplementary Table 9","description":"","filename":"SupplementaryTable9.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/402499d212e83aea4e1ba2a4.xlsx"},{"id":106402979,"identity":"267760aa-58c2-4891-9196-f8188a28a5c5","added_by":"auto","created_at":"2026-04-08 09:13:17","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":9655,"visible":true,"origin":"","legend":"Supplementary Table 12","description":"","filename":"SupplementaryTable12.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/c9ffea5d7dc3090bc8d5b80a.xlsx"},{"id":106402538,"identity":"ce38f650-8564-4e1c-9416-4c7ea45f2508","added_by":"auto","created_at":"2026-04-08 09:12:15","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":315523,"visible":true,"origin":"","legend":"Supplementary Table 6","description":"","filename":"SupplementaryTable6.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/05b7f126929b0f78fcc65357.xlsx"},{"id":106402532,"identity":"361962ba-8cdf-49e1-827f-7d954295c43e","added_by":"auto","created_at":"2026-04-08 09:12:15","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1386090,"visible":true,"origin":"","legend":"Supplementary Table 8","description":"","filename":"SupplementaryTable8.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/c731c92177a394b7c4ea28ce.xlsx"},{"id":106200400,"identity":"f9fb67f6-d706-4a6e-9829-22ff6dc91f82","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":17888,"visible":true,"origin":"","legend":"Supplementary Table 13","description":"","filename":"SupplementaryTable13.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/e8b2831af63dc3c1fe720cbe.xlsx"},{"id":106200402,"identity":"3f58e61e-ee55-48bb-838c-1239e65673b1","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":49639,"visible":true,"origin":"","legend":"Supplementary Table 10","description":"","filename":"SupplementaryTable10.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/f49a34338832285b67dfc742.xlsx"},{"id":106402792,"identity":"cb66900f-a401-4f23-8002-a90463197e4b","added_by":"auto","created_at":"2026-04-08 09:12:52","extension":"xlsx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":2056726,"visible":true,"origin":"","legend":"Supplementary Table 2","description":"","filename":"SupplementaryTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/1640342e18577993125ed791.xlsx"},{"id":106724034,"identity":"0022a48b-ad43-40ca-b2f6-56cb3373b09e","added_by":"auto","created_at":"2026-04-12 18:24:36","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1120719,"visible":true,"origin":"","legend":"Supplementary Table 7","description":"","filename":"SupplementaryTable7.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/bc9af7758da6fd0e67f68c4e.xlsx"},{"id":106200405,"identity":"732cd23d-68e3-4cad-b1ba-9bfd982d219d","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":13910,"visible":true,"origin":"","legend":"Supplementary Table 1","description":"","filename":"SupplementaryTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/20d27071aae468a3997c4ad2.xlsx"},{"id":106402477,"identity":"114c9312-76f8-471e-aaca-7d16f3134d29","added_by":"auto","created_at":"2026-04-08 09:12:07","extension":"xlsx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":14742,"visible":true,"origin":"","legend":"Supplementary Table 14","description":"","filename":"SupplementaryTable14.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/02dbe81a34881ed4466d6b6f.xlsx"},{"id":106415089,"identity":"a3dd0989-200b-4a77-b5ec-ccafeba30d5d","added_by":"auto","created_at":"2026-04-08 10:32:52","extension":"pdf","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":1673532,"visible":true,"origin":"","legend":"Reporting summary","description":"","filename":"nrreportingsummary.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/d3e773ddc0dfd2bc2b4be523.pdf"},{"id":106200407,"identity":"9a85b775-d43f-4ed5-b652-4701918dbc40","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":1784332,"visible":true,"origin":"","legend":"Supplementary Table 3","description":"","filename":"SupplementaryTable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/691b90c42b746b6e44d1003a.xlsx"},{"id":106200411,"identity":"b6f371df-5a36-4a86-9bf7-6cb096332720","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":10600,"visible":true,"origin":"","legend":"Supplementary Table 4","description":"","filename":"SupplementaryTable4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/cb7080b597ee905564745569.xlsx"},{"id":106402307,"identity":"29510797-a92b-4b94-ab96-760e5979fd64","added_by":"auto","created_at":"2026-04-08 09:11:42","extension":"xlsx","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":260141,"visible":true,"origin":"","legend":"Supplementary Table 11","description":"","filename":"SupplementaryTable11.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/13a88a9c563fc7848b843c79.xlsx"},{"id":106200408,"identity":"b290e8f8-3c24-4740-98d9-07a2f5406c31","added_by":"auto","created_at":"2026-04-06 02:45:22","extension":"xlsx","order_by":16,"title":"","display":"","copyAsset":false,"role":"supplement","size":2799551,"visible":true,"origin":"","legend":"Supplementary Table 5","description":"","filename":"SupplementaryTable5.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/657f18845e2c3c3b6ac9b2f5.xlsx"},{"id":106403442,"identity":"720c645d-ab46-4cd6-a9e7-6a6d4a260856","added_by":"auto","created_at":"2026-04-08 09:14:17","extension":"pdf","order_by":17,"title":"","display":"","copyAsset":false,"role":"supplement","size":142555,"visible":true,"origin":"","legend":"Reporting summary","description":"","filename":"rsnew.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/ae0c51b0b5c7673b04912cda.pdf"},{"id":106402616,"identity":"bdc01125-28d9-4b1e-b5ab-b1e1b5ef7b93","added_by":"auto","created_at":"2026-04-08 09:12:26","extension":"zip","order_by":18,"title":"","display":"","copyAsset":false,"role":"supplement","size":11830876,"visible":true,"origin":"","legend":"Supp Data ZIP","description":"","filename":"sourcedata1.zip","url":"https://assets-eu.researchsquare.com/files/rs-6009404/v1/2e2ad76b203ad720962c370c.zip"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"glioblastoma, matrix stiffness, radiation, IQGAP3, SOX2, cancer stem cell, glioma stem cell","lastPublishedDoi":"10.21203/rs.3.rs-6009404/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6009404/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Drivers of therapeutic resistance in cancer include evolving tumor cell heterogeneity and the tumor microenvironment (TME). Here, we found that increased matrix stiffness promotes radioresistance in glioblastoma (GBM) and maintains tumor cell hierarchies. Differential gene expression revealed that stiff matrices induced expression of IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) through YAP1 and TEAD transcription factors in GBM stem cells (GSCs). IQGAP3 promoted GSC self-renewal and survival upon radiation treatment through binding and stabilization of core stem cell transcription factor, SOX2. Targeting IQGAP3 reduced SOX2 protein levels in vitro and in vivo, increasing GSC radiosensitivity and inhibiting tumor growth. Structure-function drug screening of FDA-approved agents blocking IQGAP3-SOX2 binding identified trimetrexate as a brain penetrant pharmacologic disruptor of IQGAP3 function in radioresistance, sensitizing GSCs to radiotherapy. These results identify molecular underpinnings for biomechanical promotion of cancer stem cell maintenance and therapeutic resistance, informing therapeutic strategies to augment efficacy of radiotherapy.","manuscriptTitle":"IQGAP3 bridges matrix stiffness with glioma stem cell maintenance and radioresistance by stabilizing SOX2","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-06 02:45:09","doi":"10.21203/rs.3.rs-6009404/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"158b583c-a728-4ac1-884a-af586cd1c6af","owner":[],"postedDate":"April 6th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64864823,"name":"Biological sciences/Cancer/CNS cancer"},{"id":64864824,"name":"Biological sciences/Cancer/Cancer stem cells"}],"tags":[],"updatedAt":"2026-05-07T01:00:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-06 02:45:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6009404","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6009404","identity":"rs-6009404","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}