Heterogeneity of collagen and collagen-fibronectin networks promotes invasive behavior of liver cancer cells

Heterogeneity of collagen and collagen-fibronectin networks promotes invasive behavior of liver cancer cells | 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 Research Article Heterogeneity of collagen and collagen-fibronectin networks promotes invasive behavior of liver cancer cells Alexander Hayn, Madlen Matz-Soja, Thomas Berg, Florian van Bömmel This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7932565/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Purpose The remodeling of the extracellular matrix (ECM) is a key feature of tumor development in the liver, particularly in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Fibrosis and cirrhosis are risk factors for tumorigenesis and define serious structural changes in the ECM. Fibrotic-induced collagen and fibronectin alter the stiffness and heterogeneity of the ECM. A stiffened and heterogeneous ECM promotes the proliferation, migration, and invasion of tumor cells. Direct effects of structural changes in the ECM on HCC / iCCA cancer cells are insufficiently studied. Methods HCC and iCCA cells were examined in contact with varying structurally heterogeneous collagen and collagen-fibronectin networks. Heterogeneity of the networks was defined by the combination of stiffness and intrinsic properties. Network heterogeneity-related effects of cell-matrix interactions on cell stiffness, invasiveness, and the ability to interact with network structures by fiber displacements were determined. Results Increased network heterogeneity caused a decrease in cell stiffness, an increase in cell invasiveness, and altered fiber displacements. Different effects on HCC and iCCA cells depending on network heterogeneity were identified. High ECM heterogeneity resulted in low cell stiffness and high cell invasion across cancer cell types. Conclusions We present a model system that is applicable to identify structurally induced influences of the extracellular matrix on cancer cells and to investigate the risk factor of structural changes in the tumor environment. Extracellular matrix fibrosis hepatocellular carcinoma intrahepatic cholangiocarcinoma Full Text Additional Declarations No competing interests reported. Supplementary Files SV1lessnetworkheterogeneitycollagen.mp4 SV2lessnetworkheterogeneitycollagenfibronectin.mp4 SV3increasednetworkheterogeneitycollagen.mp4 SV4increasednetworkheterogeneitycollagenfibronectin.mp4 SV5highnetworkheterogeneitycollagen.mp4 SV6highnetworkheterogeneitycollagenfibronectin.mp4 Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 01 Dec, 2025 Reviews received at journal 19 Nov, 2025 Reviews received at journal 18 Nov, 2025 Reviews received at journal 13 Nov, 2025 Reviews received at journal 12 Nov, 2025 Reviewers agreed at journal 02 Nov, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers agreed at journal 29 Oct, 2025 Reviewers agreed at journal 28 Oct, 2025 Reviewers invited by journal 28 Oct, 2025 Editor assigned by journal 24 Oct, 2025 Submission checks completed at journal 24 Oct, 2025 First submitted to journal 23 Oct, 2025 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. 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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-7932565","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":538763009,"identity":"772e885d-800d-4a25-b4bf-83a83538427f","order_by":0,"name":"Alexander 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cells","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"cellular-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ceon","sideBox":"Learn more about [Cellular Oncology](http://link.springer.com/journal/13402)","snPcode":"13402","submissionUrl":"https://submission.nature.com/new-submission/13402/3","title":"Cellular Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Extracellular matrix, fibrosis, hepatocellular carcinoma, intrahepatic cholangiocarcinoma","lastPublishedDoi":"10.21203/rs.3.rs-7932565/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7932565/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eThe remodeling of the extracellular matrix (ECM) is a key feature of tumor development in the liver, particularly in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Fibrosis and cirrhosis are risk factors for tumorigenesis and define serious structural changes in the ECM. Fibrotic-induced collagen and fibronectin alter the stiffness and heterogeneity of the ECM. A stiffened and heterogeneous ECM promotes the proliferation, migration, and invasion of tumor cells. Direct effects of structural changes in the ECM on HCC / iCCA cancer cells are insufficiently studied.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eHCC and iCCA cells were examined in contact with varying structurally heterogeneous collagen and collagen-fibronectin networks. Heterogeneity of the networks was defined by the combination of stiffness and intrinsic properties. Network heterogeneity-related effects of cell-matrix interactions on cell stiffness, invasiveness, and the ability to interact with network structures by fiber displacements were determined.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eIncreased network heterogeneity caused a decrease in cell stiffness, an increase in cell invasiveness, and altered fiber displacements. Different effects on HCC and iCCA cells depending on network heterogeneity were identified. High ECM heterogeneity resulted in low cell stiffness and high cell invasion across cancer cell types.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eWe present a model system that is applicable to identify structurally induced influences of the extracellular matrix on cancer cells and to investigate the risk factor of structural changes in the tumor environment.\u003c/p\u003e","manuscriptTitle":"Heterogeneity of collagen and collagen-fibronectin networks promotes invasive behavior of liver cancer cells","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-07 18:31:26","doi":"10.21203/rs.3.rs-7932565/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-01T15:04:22+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-19T17:10:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-18T20:43:58+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-13T17:51:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-13T02:22:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"91169929922010588289407318092017320693","date":"2025-11-02T18:05:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242032272899240811309547860146077794876","date":"2025-10-29T13:04:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225413586768448088835481541731493470970","date":"2025-10-29T12:31:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"202786366610490384039010689089126795850","date":"2025-10-29T00:42:46+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-28T17:58:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-24T17:11:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-24T12:12:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular Oncology","date":"2025-10-23T13:07:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ceon","sideBox":"Learn more about [Cellular Oncology](http://link.springer.com/journal/13402)","snPcode":"13402","submissionUrl":"https://submission.nature.com/new-submission/13402/3","title":"Cellular Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a71de20e-594c-4c3e-a613-fb45674056a6","owner":[],"postedDate":"November 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-11T12:59:14+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-07 18:31:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7932565","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7932565","identity":"rs-7932565","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}