Hypoxia drives the formation of lung micropapillary adenocarcinoma through hypoxia-inducible factor-1α

Hypoxia drives the formation of lung micropapillary adenocarcinoma through hypoxia-inducible factor-1α | 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 Hypoxia drives the formation of lung micropapillary adenocarcinoma through hypoxia-inducible factor-1α Satoshi Nojima, Daisuke Umeda, Akikazu Harada, Koto Ukon, Daisuke Motooka, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4508444/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Dec, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Micropapillary adenocarcinoma (MPC) is an aggressive histologic subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Spatial transcriptome (ST) analysis with human LUAD tissue suggested that hypoxia-inducible factor (HIF)-1 signaling is activated in MPC. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited high expression of the MPC signature genes, which were defined by the ST data. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. Our findings suggest that hypoxia drives lung MPC formation through HIF-1α and that immune escape from natural killer cells might underlie the aggressiveness of MPC. Biological sciences/Cancer/Cancer models Biological sciences/Cancer/Lung cancer lung micropapillary adenocarcinoma hypoxia Matrigel three-dimensional cell culture hypoxia-inducible factor-1α MUC1 Rho Rho-kinase natural killer cell cytotoxicity Full Text Additional Declarations No competing interests reported. Supplementary Files Umedaetal.Supplementaryinformation240612.pdf Cite Share Download PDF Status: Published Journal Publication published 30 Dec, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 30 Jul, 2024 Reviews received at journal 15 Jul, 2024 Reviewers agreed at journal 13 Jul, 2024 Reviews received at journal 24 Jun, 2024 Reviewers agreed at journal 21 Jun, 2024 Reviewers invited by journal 20 Jun, 2024 Editor assigned by journal 20 Jun, 2024 Editor invited by journal 12 Jun, 2024 Submission checks completed at journal 12 Jun, 2024 First submitted to journal 31 May, 2024 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. 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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-4508444","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":319057543,"identity":"3ffd590b-02d0-441f-99f4-3dd79c14dab7","order_by":0,"name":"Satoshi 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adenocarcinoma, hypoxia, Matrigel, three-dimensional cell culture, hypoxia-inducible factor-1α, MUC1, Rho, Rho-kinase, natural killer cell cytotoxicity","lastPublishedDoi":"10.21203/rs.3.rs-4508444/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4508444/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Micropapillary adenocarcinoma (MPC) is an aggressive histologic subtype of lung adenocarcinoma (LUAD). MPC is composed of small clusters of cancer cells exhibiting inverted polarity. However, the mechanism underlying its formation is poorly understood. Here we show that hypoxia is involved in MPC formation. Spatial transcriptome (ST) analysis with human LUAD tissue suggested that hypoxia-inducible factor (HIF)-1 signaling is activated in MPC. Hypoxia induced the formation of MPC-like structures (MLSs) in a three-dimensional culture system using A549 human LUAD cells, and HIF-1α was indispensable for MLS formation. RNA sequencing analysis demonstrated that A549 cells forming MLSs exhibited high expression of the MPC signature genes, which were defined by the ST data. Moreover, MLS formation enhanced the resistance of A549 cells to natural killer cell cytotoxicity. 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