Targeting OFD1 restrains KRAS-driven pancreatic cancer progression by impairing macropinocytosis

Targeting OFD1 restrains KRAS-driven pancreatic cancer progression by impairing macropinocytosis | 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 Targeting OFD1 restrains KRAS-driven pancreatic cancer progression by impairing macropinocytosis Qing Zhong, Peng Li, Qian Yang, Zaiming Tang, Junjie Ye, Yi Pan, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8939646/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy driven by oncogenic KRAS and characterized by profound metabolic rewiring. To sustain proliferation under nutrient stress, PDAC cells rely on macropinocytosis, an cytoskeleton-dependent pathway for extracellular nutrient uptake. The Oral-Facial-Digital syndrome 1 protein OFD1 is implicated in the progression of PDAC and regulates actin cytoskeletal dynamics. However, its role in macropinocytosis remains unclear. Here, we identify OFD1 as a key downstream effector of KRAS that orchestrates macropinocytosis. The oncogenic KRAS induces OFD1 expression, wheras OFD1 depletion markedly impairs macropinocytic activity and consequently suppresses tumor growth in KRAS mutant PDAC xenograft models. Mechanistically, OFD1 sustains NF-κB-dependent transcription of Syndecan-4 (SDC4), a core component of the macropinocytic machinery. In turn, restoration of SDC4 expression rescues macropinocytosis and tumor growth. Notably, a drug-repurposing screen identifies pharmacological degradation of OFD1 as an effective strategy to inhibit macropinocytosis and restrain PDAC progression. Consistent with these findings, OFD1 expression positively correlates with SDC4 levels in PDAC patient samples, and elevated SDC4 expression is associated with poor patient survival. Together, these findings establish OFD1 as a central regulator of macropinocytosis and reveal a potential metabolic vulnerability in PDAC. Biological sciences/Cancer/Gastrointestinal cancer/Pancreatic cancer Biological sciences/Cancer/Cancer metabolism Biological sciences/Cancer/Oncogenes OFD1 Macropinocytosis KRAS pancreatic cancer SDC4 Full Text Additional Declarations (Not answered) Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: revise 10 Apr, 2026 Review # 2 received at journal 28 Mar, 2026 Reviewer # 2 agreed at journal 18 Mar, 2026 Review # 1 received at journal 09 Mar, 2026 Reviewer # 1 agreed at journal 05 Mar, 2026 Reviewers invited by journal 04 Mar, 2026 Submission checks completed at journal 23 Feb, 2026 Editor assigned by journal 22 Feb, 2026 First submitted to journal 22 Feb, 2026 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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To sustain proliferation under nutrient stress, PDAC cells rely on macropinocytosis, an cytoskeleton-dependent pathway for extracellular nutrient uptake. The Oral-Facial-Digital syndrome 1 protein OFD1 is implicated in the progression of PDAC and regulates actin cytoskeletal dynamics. However, its role in macropinocytosis remains unclear. Here, we identify OFD1 as a key downstream effector of KRAS that orchestrates macropinocytosis. The oncogenic KRAS induces OFD1 expression, wheras OFD1 depletion markedly impairs macropinocytic activity and consequently suppresses tumor growth in KRAS mutant PDAC xenograft models. Mechanistically, OFD1 sustains NF-κB-dependent transcription of Syndecan-4 (SDC4), a core component of the macropinocytic machinery. In turn, restoration of SDC4 expression rescues macropinocytosis and tumor growth. Notably, a drug-repurposing screen identifies pharmacological degradation of OFD1 as an effective strategy to inhibit macropinocytosis and restrain PDAC progression. Consistent with these findings, OFD1 expression positively correlates with SDC4 levels in PDAC patient samples, and elevated SDC4 expression is associated with poor patient survival. Together, these findings establish OFD1 as a central regulator of macropinocytosis and reveal a potential metabolic vulnerability in PDAC.","manuscriptTitle":"Targeting OFD1 restrains KRAS-driven pancreatic cancer progression by impairing macropinocytosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-09 13:33:40","doi":"10.21203/rs.3.rs-8939646/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2026-04-10T15:10:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-28T04:56:45+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-19T03:50:50+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-03-09T12:10:07+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-03-05T09:03:52+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2026-03-04T23:00:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-23T14:51:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-22T14:08:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cell Death \u0026 Disease","date":"2026-02-22T14:08:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cell-death-and-disease","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"cddis","sideBox":"Learn more about [Cell Death \u0026 Disease](http://www.nature.com/cddis/)","snPcode":"41419","submissionUrl":"https://mts-cddis.nature.com/cgi-bin/main.plex","title":"Cell Death \u0026 Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2c2ef226-3e22-4c00-9efa-13ac7f1a38c3","owner":[],"postedDate":"March 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":63946523,"name":"Biological sciences/Cancer/Gastrointestinal cancer/Pancreatic cancer"},{"id":63946524,"name":"Biological sciences/Cancer/Cancer metabolism"},{"id":63946525,"name":"Biological sciences/Cancer/Oncogenes"}],"tags":[],"updatedAt":"2026-04-10T15:26:57+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-09 13:33:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8939646","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8939646","identity":"rs-8939646","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}