ARF6-AMAP1 pathway induces pancreatic cancer cells to express immunosuppressive chemokines

ARF6-AMAP1 pathway induces pancreatic cancer cells to express immunosuppressive chemokines | 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 Short Report ARF6-AMAP1 pathway induces pancreatic cancer cells to express immunosuppressive chemokines Ari Hashimoto, Haruka Handa, Soichiro Hata, Daisuke Okuzaki, Yoshizuki Fumoto, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1897319/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 Aim: The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is highly immune suppressive with modest T-cell infiltration, and only rarely responds to immune checkpoint inhibition (ICI) therapy. Our aim was to clarify the molecular basis underlying the immune suppressive properties of PDAC. Background: Mutations in both KRAS and TP53 genes are characteristic of PDAC. A major target of KRAS/TP53 double mutations is the ARF6-AMAP1 pathway, which promotes the fibrosis, acidosis, invasion, and immune evasion of cancer cells. KPC cells are a genetically well-defined mouse cell model of human PDAC bearing Kras/Trp53 mutations, and express Arf6 and Amap1 at high levels. Findings: Intact KPC cells predominantly expressed immune suppressive chemokines, such as Cxcl12 and Cxcl5, but when Amap1 was silenced, immune surveillance chemokines, such as Cxcl10 and Ccl5 became predominant. A similar, albeit fragmented, chemokine switching was observed in human PDAC cells, and this mechanism appeared to be used in the normal pancreas of humans and mice. The silencing of Amap1 in KPC cells significantly changed the types and numbers of tumor infiltrating lymphocytes to be less favorable for immune evasion. Conclusions: Many PDAC cells appear to have a hitherto unidentified mechanism of malignancy, by which they can change the types of chemokines that they produce to be favorable for immune evasion. The ARF6-AMAP1 pathway is integral to this chemokine switching. Hence, this malignancy appears to be the result of KRAS/TP53 double mutations, which are not common in other types of cancer unless they are in the advanced stages. Our results are consistent with our previous findings that blockade of the ARF6- AMAP1 pathway significantly improves the efficacy of ICI therapy. Chemokine Pancreatic cancer Arf6 Immune evasion Cancer plasticity Full Text Additional Declarations No competing interests reported. Supplementary Files SuppleFigure1Hashimotoetal.pdf 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. 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-1897319","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":124322861,"identity":"51a71f5b-d902-4107-a46b-3c3210694ac9","order_by":0,"name":"Ari Hashimoto","email":"","orcid":"","institution":"Hokkaido University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ari","middleName":"","lastName":"Hashimoto","suffix":""},{"id":124322863,"identity":"9984e382-a3f5-4591-9c7d-63c2c4cdac56","order_by":1,"name":"Haruka Handa","email":"","orcid":"","institution":"Hokkaido University Faculty of 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yoshihiro","middleName":"","lastName":"Nishikawa","suffix":""},{"id":124322875,"identity":"421c89b8-36dc-407f-a35c-1552cfe85096","order_by":8,"name":"Yuzo Kodama","email":"","orcid":"","institution":"Kobe University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yuzo","middleName":"","lastName":"Kodama","suffix":""},{"id":124322877,"identity":"60908522-4e5a-4ca7-a02d-73ec2c629e02","order_by":9,"name":"Satoshi Hirano","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Hirano","suffix":""},{"id":124322879,"identity":"2a4c621a-7566-4fac-b1dc-b71f86267fa8","order_by":10,"name":"Shigeru Hashimoto","email":"","orcid":"","institution":"Hokkaido University","correspondingAuthor":false,"prefix":"","firstName":"Shigeru","middleName":"","lastName":"Hashimoto","suffix":""},{"id":124322881,"identity":"4ab6b089-ebeb-4de2-b221-e9c7b1e66a58","order_by":11,"name":"Hisataka Sabe","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYFACHgZmhgogfYCHgbEByGaDihLQcoZkLYxtSFoIAvn2swcfF87bJsd3gPfgw5lt1vJ8DMwPPzDI3MGpxeBMXrLxzG23jSUP8CUbbmxLN2xjYDOWYOB5hlsLQ46ZNO+224kbDvCYST5sOwxypBnQuYdxO6z/jflv3jm362Fa7NsY2L/h1cJwI8eMmbfhdoIBSMvGtsOJbQw8+G0xuPEuWZrn2G3DmYd5jA1nnEtPbmPmKZZIwOMX+f7cg595am7L8x3vMXzYU2ZtO7+9feOHjz24QwwBmJEZiT0HiNCCCn6QrmUUjIJRMAqGLQAA/hFTm2srXcYAAAAASUVORK5CYII=","orcid":"","institution":"Hokkaido University Faculty of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hisataka","middleName":"","lastName":"Sabe","suffix":""}],"badges":[],"createdAt":"2022-07-26 10:44:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1897319/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1897319/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":24616156,"identity":"f9582b53-9027-418a-b4f2-6d1e0238fef4","added_by":"auto","created_at":"2022-08-01 17:57:26","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1625207,"visible":true,"origin":"","legend":"","description":"","filename":"MSHashimotoetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1897319/v1_covered.pdf"},{"id":24616150,"identity":"38e865b0-e1a5-4e93-900f-de3e85959015","added_by":"auto","created_at":"2022-08-01 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plasticity","lastPublishedDoi":"10.21203/rs.3.rs-1897319/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1897319/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eAim: \u003c/strong\u003eThe tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is highly immune suppressive with modest T-cell infiltration, and only rarely responds to immune checkpoint inhibition (ICI) therapy. Our aim was to clarify the molecular basis underlying the immune suppressive properties of PDAC.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Mutations in both KRAS and TP53 genes are characteristic of PDAC. A major target of KRAS/TP53 double mutations is the ARF6-AMAP1 pathway, which promotes the fibrosis, acidosis, invasion, and immune evasion of cancer cells. KPC cells are a genetically well-defined mouse cell model of human PDAC bearing Kras/Trp53 mutations, and express Arf6 and Amap1 at high levels.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eFindings: \u003c/strong\u003eIntact KPC cells predominantly expressed immune suppressive chemokines, such as Cxcl12 and Cxcl5, but when Amap1 was silenced, immune surveillance chemokines, such as Cxcl10 and Ccl5 became predominant. A similar, albeit fragmented, chemokine switching was observed in human PDAC cells, and this mechanism appeared to be used in the normal pancreas of humans and mice. The silencing of Amap1 in KPC cells significantly changed the types and numbers of tumor infiltrating lymphocytes to be less favorable for immune evasion.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eMany PDAC cells appear to have a hitherto unidentified mechanism of malignancy, by which they can change the types of chemokines that they produce to be favorable for immune evasion. The ARF6-AMAP1 pathway is integral to this chemokine switching. Hence, this malignancy appears to be the result of KRAS/TP53 double mutations, which are not common in other types of cancer unless they are in the advanced stages. Our results are consistent with our previous findings that blockade of the ARF6- AMAP1 pathway significantly improves the efficacy of ICI therapy.\u003c/p\u003e","manuscriptTitle":"ARF6-AMAP1 pathway induces pancreatic cancer cells to express immunosuppressive chemokines","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-01 17:57:18","doi":"10.21203/rs.3.rs-1897319/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":"6dfb4de0-4372-407d-a0bb-641cbfa0a2d3","owner":[],"postedDate":"August 1st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-04-25T03:59:18+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-01 17:57:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1897319","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1897319","identity":"rs-1897319","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}