{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:42:05Z","timestamp":1790959325842,"version":"4.1.0"},"posted":{"date-parts":[[2024,7,30]]},"group-title":"Cancer Biology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,7,30]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identified senescent\n                  <jats:italic>\n                    p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                  <\/jats:italic>\n                  + cancer-associated fibroblasts with a secretory phenotype that promotes fatty acid uptake and utilization by aggressive lung adenocarcinoma driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by\n                  <jats:italic>\n                    p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                  <\/jats:italic>\n                  + cancer- associated fibroblasts also altered tumor cell identity to a highly plastic\/dedifferentiated state associated with progression in murine and human LUAD. Our\n                  <jats:italic>ex vivo<\/jats:italic>\n                  senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared\n                  <jats:italic>\n                    p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                  <\/jats:italic>\n                  + cancer- associated fibroblasts\n                  <jats:italic>in vivo<\/jats:italic>\n                  . XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.\n                <\/jats:p>","DOI":"10.1101\/2024.07.29.605645","type":"posted-content","created":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T12:50:39Z","timestamp":1722343839000},"source":"Crossref","is-referenced-by-count":3,"title":["Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity"],"prefix":"10.64898","author":[{"given":"Jin Young","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabora","family":"Reyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Ho","family":"Woo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakshi","family":"Goel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fia","family":"Stratton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyuan","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron S.","family":"Mansfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay M.","family":"LaFave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tien","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024080108301372000_2024.07.29.605645v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183653"},{"key":"2024080108301372000_2024.07.29.605645v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.211053698"},{"key":"2024080108301372000_2024.07.29.605645v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.95"},{"key":"2024080108301372000_2024.07.29.605645v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.06.006"},{"key":"2024080108301372000_2024.07.29.605645v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.06.012"},{"key":"2024080108301372000_2024.07.29.605645v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.06.020"},{"key":"2024080108301372000_2024.07.29.605645v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-0542-8"},{"key":"2024080108301372000_2024.07.29.605645v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17358-3"},{"key":"2024080108301372000_2024.07.29.605645v1.9","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf3326"},{"key":"2024080108301372000_2024.07.29.605645v1.10","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0094"},{"key":"2024080108301372000_2024.07.29.605645v1.11","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0644"},{"key":"2024080108301372000_2024.07.29.605645v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.10.005"},{"key":"2024080108301372000_2024.07.29.605645v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0238-1"},{"key":"2024080108301372000_2024.07.29.605645v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.06.043"},{"key":"2024080108301372000_2024.07.29.605645v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0667-5"},{"key":"2024080108301372000_2024.07.29.605645v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2023.05.002"},{"key":"2024080108301372000_2024.07.29.605645v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.07.009"},{"key":"2024080108301372000_2024.07.29.605645v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0650-z"},{"key":"2024080108301372000_2024.07.29.605645v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03549-5"},{"key":"2024080108301372000_2024.07.29.605645v1.20","doi-asserted-by":"publisher","DOI":"10.1172\/JCI173371"},{"key":"2024080108301372000_2024.07.29.605645v1.21","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12445"},{"key":"2024080108301372000_2024.07.29.605645v1.22","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12344"},{"key":"2024080108301372000_2024.07.29.605645v1.23","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1714"},{"key":"2024080108301372000_2024.07.29.605645v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07113-9"},{"key":"2024080108301372000_2024.07.29.605645v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(61)90192-6"},{"key":"2024080108301372000_2024.07.29.605645v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.07.022"},{"key":"2024080108301372000_2024.07.29.605645v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.08.028"},{"key":"2024080108301372000_2024.07.29.605645v1.28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1617709114"},{"key":"2024080108301372000_2024.07.29.605645v1.29","doi-asserted-by":"publisher","DOI":"10.1101\/gad.943001"},{"key":"2024080108301372000_2024.07.29.605645v1.30","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2193"},{"key":"2024080108301372000_2024.07.29.605645v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2467"},{"key":"2024080108301372000_2024.07.29.605645v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf3326"},{"key":"2024080108301372000_2024.07.29.605645v1.33","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/nprot.2009.95","article-title":"Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase","volume":"4","year":"2009","journal-title":"Nature protocols"},{"key":"2024080108301372000_2024.07.29.605645v1.34","doi-asserted-by":"crossref","unstructured":"Lee, J.Y. , Reyes, N.S. , Ravishankar, S. , Zhou, M. , Krasilnikov, M. , Ringler, C. , Pohan, G. , Wilson, C. , Ang, K.K.-H. , and Wolters, P.J . (2024). An in vivo screening platform identifies senolytic compounds that target p16 INK4a+ fibroblasts in lung fibrosis. The Journal of Clinical Investigation.","DOI":"10.1172\/JCI173371"},{"key":"2024080108301372000_2024.07.29.605645v1.35","doi-asserted-by":"crossref","first-page":"8353","DOI":"10.1038\/s41467-023-43458-x","article-title":"High resolution mapping of the tumor microenvironment using integrated single-cell, spatial and in situ analysis","volume":"14","year":"2023","journal-title":"Nature Communications"},{"key":"2024080108301372000_2024.07.29.605645v1.36","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2018100300"},{"key":"2024080108301372000_2024.07.29.605645v1.37","first-page":"648","article-title":"High sensitivity quantitative lipidomics analysis of fatty acids in biological samples by gas chromatography\u2013mass spectrometry","volume":"1811","year":"2011","journal-title":"Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids"},{"key":"2024080108301372000_2024.07.29.605645v1.38","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1038\/s41598-022-06841-0","article-title":"Survival Genie, a web platform for survival analysis across pediatric and adult cancers","volume":"12","year":"2022","journal-title":"Scientific Reports"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.07.29.605645","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:47:27Z","timestamp":1768459647000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.07.29.605645"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,30]]},"references-count":38,"URL":"https:\/\/doi.org\/10.1101\/2024.07.29.605645","relation":{},"subject":[],"published":{"date-parts":[[2024,7,30]]},"subtype":"preprint"}}