{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T12:54:49Z","timestamp":1794315289629,"version":"4.9.0"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-50441-7","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T07:06:55Z","timestamp":1721632015000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice"],"prefix":"10.1038","volume":"15","author":[{"given":"Benjamin","family":"Assouline","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Kahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lutfi","family":"Hodali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reba","family":"Condiotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yarden","family":"Engel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ela","family":"Elyada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzlil","family":"Mordechai-Heyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R.","family":"Pitarresi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3362-025X","authenticated-orcid":false,"given":"Dikla","family":"Atias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Steinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tirza","family":"Bidany-Mizrahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Forkosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior H.","family":"Katz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2468-5978","authenticated-orcid":false,"given":"Ofra","family":"Benny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talia","family":"Golan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matan","family":"Hofree","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-9576","authenticated-orcid":false,"given":"Sheila A.","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine A.","family":"Atlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gideon","family":"Zamir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0410-4037","authenticated-orcid":false,"given":"Ben Z.","family":"Stanger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3469-0076","authenticated-orcid":false,"given":"Michael","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7815-1165","authenticated-orcid":false,"given":"Ittai","family":"Ben-Porath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"50441_CR1","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.cell.2017.05.015","volume":"169","author":"S He","year":"2017","unstructured":"He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000\u20131011 (2017).","journal-title":"Cell"},{"key":"50441_CR2","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","volume":"179","author":"V Gorgoulis","year":"2019","unstructured":"Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813\u2013827 (2019).","journal-title":"Cell"},{"key":"50441_CR3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1038\/s41580-020-00314-w","volume":"22","author":"R Di Micco","year":"2021","unstructured":"Di Micco, R., Krizhanovsky, V., Baker, D. & d\u2019Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75\u201395 (2021).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"50441_CR4","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/nrc2772","volume":"10","author":"M Collado","year":"2009","unstructured":"Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10, 51\u201357 (2009).","journal-title":"Nat. Rev. Cancer"},{"key":"50441_CR5","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nrc3773","volume":"14","author":"PA Perez-Mancera","year":"2014","unstructured":"Perez-Mancera, P. A., Young, A. R. & Narita, M. Inside and out: the activities of senescence in cancer. Nat. Rev. Cancer 14, 547\u2013558 (2014).","journal-title":"Nat. Rev. Cancer"},{"key":"50441_CR6","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/s41556-018-0249-2","volume":"21","author":"S Lee","year":"2019","unstructured":"Lee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. Cell Biol. 21, 94\u2013101 (2019).","journal-title":"Nat. Cell Biol."},{"key":"50441_CR7","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/s41568-019-0156-2","volume":"19","author":"DV Faget","year":"2019","unstructured":"Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439\u2013453 (2019).","journal-title":"Nat. Rev. Cancer"},{"key":"50441_CR8","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.trecan.2022.09.002","volume":"9","author":"Y Gabai","year":"2023","unstructured":"Gabai, Y., Assouline, B. & Ben-Porath, I. Senescent stromal cells: roles in the tumor microenvironment. Trends Cancer 9, 28\u201341 (2023).","journal-title":"Trends Cancer"},{"key":"50441_CR9","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/s41568-022-00450-9","volume":"22","author":"L Wang","year":"2022","unstructured":"Wang, L., Lankhorst, L. & Bernards, R. Exploiting senescence for the treatment of cancer. Nat. Rev. Cancer 22, 340\u2013355 (2022).","journal-title":"Nat. Rev. Cancer"},{"key":"50441_CR10","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1038\/nature05529","volume":"445","author":"W Xue","year":"2007","unstructured":"Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656\u2013660 (2007).","journal-title":"Nature"},{"key":"50441_CR11","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1038\/nature10599","volume":"479","author":"TW Kang","year":"2011","unstructured":"Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547\u2013551 (2011).","journal-title":"Nature"},{"key":"50441_CR12","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1126\/science.aas9090","volume":"362","author":"M Ruscetti","year":"2018","unstructured":"Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416\u20131422 (2018).","journal-title":"Science"},{"key":"50441_CR13","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1158\/2159-8290.CD-22-0528","volume":"13","author":"HA Chen","year":"2023","unstructured":"Chen, H. A. et al. Senescence rewires microenvironment sensing to facilitate anti-tumor immunity. Cancer Discov. 13, 432\u2013453 (2023).","journal-title":"Cancer Discov."},{"key":"50441_CR14","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1158\/2159-8290.CD-22-0523","volume":"13","author":"I Marin","year":"2023","unstructured":"Marin, I. et al. Cellular senescence is immunogenic and promotes anti-tumor immunity. Cancer Discov. 13, 410\u2013431 (2023).","journal-title":"Cancer Discov."},{"key":"50441_CR15","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/nature12347","volume":"499","author":"S Yoshimoto","year":"2013","unstructured":"Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97\u2013101 (2013).","journal-title":"Nature"},{"key":"50441_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11762","volume":"7","author":"MK Ruhland","year":"2016","unstructured":"Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016).","journal-title":"Nat. Commun."},{"key":"50441_CR17","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1158\/2159-8290.CD-16-0241","volume":"7","author":"M Demaria","year":"2017","unstructured":"Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165\u2013176 (2017).","journal-title":"Cancer Discov."},{"key":"50441_CR18","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1136\/gutjnl-2020-321112","volume":"71","author":"D Kolodkin-Gal","year":"2021","unstructured":"Kolodkin-Gal, D. et al. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut 71, 345\u2013355 (2021).","journal-title":"Gut"},{"key":"50441_CR19","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1016\/j.cell.2023.02.014","volume":"186","author":"CJ Halbrook","year":"2023","unstructured":"Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M. & Maitra, A. Pancreatic cancer: advances and challenges. Cell 186, 1729\u20131754 (2023).","journal-title":"Cell"},{"key":"50441_CR20","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/s41568-022-00530-w","volume":"23","author":"SR Hingorani","year":"2023","unstructured":"Hingorani, S. R. Epithelial and stromal co-evolution and complicity in pancreatic cancer. Nat. Rev. Cancer 23, 57\u201377 (2023).","journal-title":"Nat. Rev. Cancer"},{"key":"50441_CR21","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/s43018-022-00411-z","volume":"3","author":"D Lavie","year":"2022","unstructured":"Lavie, D., Ben-Shmuel, A., Erez, N. & Scherz-Shouval, R. Cancer-associated fibroblasts in the single-cell era. Nat. Cancer 3, 793\u2013807 (2022).","journal-title":"Nat. Cancer"},{"key":"50441_CR22","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1084\/jem.20162024","volume":"214","author":"D Ohlund","year":"2017","unstructured":"Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579\u2013596 (2017).","journal-title":"J. Exp. Med."},{"key":"50441_CR23","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1158\/2159-8290.CD-19-0094","volume":"9","author":"E Elyada","year":"2019","unstructured":"Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102\u20131123 (2019).","journal-title":"Cancer Discov."},{"key":"50441_CR24","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1158\/2159-8290.CD-20-1484","volume":"12","author":"KM McAndrews","year":"2022","unstructured":"McAndrews, K. M. et al. Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL6-mediated therapy resistance in pancreatic cancer. Cancer Discov. 12, 1580\u20131597 (2022).","journal-title":"Cancer Discov."},{"key":"50441_CR25","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1016\/j.ccell.2021.06.017","volume":"39","author":"C Hutton","year":"2021","unstructured":"Hutton, C. et al. Single-cell analysis defines a pancreatic fibroblast lineage that supports anti-tumor immunity. Cancer Cell 39, 1227\u20131244.e1220 (2021).","journal-title":"Cancer Cell"},{"key":"50441_CR26","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1158\/2159-8290.CD-19-0644","volume":"10","author":"CX Dominguez","year":"2020","unstructured":"Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232\u2013253 (2020).","journal-title":"Cancer Discov."},{"key":"50441_CR27","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.ccr.2011.05.011","volume":"19","author":"C Guerra","year":"2011","unstructured":"Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728\u2013739 (2011).","journal-title":"Cancer Cell"},{"key":"50441_CR28","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.1038\/onc.2011.350","volume":"31","author":"ME Caldwell","year":"2012","unstructured":"Caldwell, M. E. et al. Cellular features of senescence during the evolution of human and murine ductal pancreatic cancer. Oncogene 31, 1599\u20131608 (2012).","journal-title":"Oncogene"},{"key":"50441_CR29","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.cell.2020.03.008","volume":"181","author":"M Ruscetti","year":"2020","unstructured":"Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424\u2013441.e421 (2020).","journal-title":"Cell"},{"key":"50441_CR30","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.ccr.2012.10.025","volume":"22","author":"JL Kopp","year":"2012","unstructured":"Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737\u2013750 (2012).","journal-title":"Cancer Cell"},{"key":"50441_CR31","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/s41422-019-0195-y","volume":"29","author":"J Peng","year":"2019","unstructured":"Peng, J. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 29, 725\u2013738 (2019).","journal-title":"Cell Res."},{"key":"50441_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29824-1","volume":"13","author":"M Troiani","year":"2022","unstructured":"Troiani, M. et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nat. Commun. 13, 2177 (2022).","journal-title":"Nat. Commun."},{"key":"50441_CR33","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1016\/j.molmet.2015.09.008","volume":"4","author":"M Benazra","year":"2015","unstructured":"Benazra, M. et al. A human beta cell line with drug inducible excision of immortalizing transgenes. Mol. Metab. 4, 916\u2013925 (2015).","journal-title":"Mol. Metab."},{"key":"50441_CR34","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.immuni.2018.06.006","volume":"49","author":"J Li","year":"2018","unstructured":"Li, J. et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49, 178\u2013193.e177 (2018).","journal-title":"Immunity"},{"key":"50441_CR35","doi-asserted-by":"publisher","first-page":"5577","DOI":"10.1016\/j.cell.2021.09.022","volume":"184","author":"BT Grunwald","year":"2021","unstructured":"Grunwald, B. T. et al. Spatially confined sub-tumor microenvironments in pancreatic cancer. Cell 184, 5577\u20135592.e5518 (2021).","journal-title":"Cell"},{"key":"50441_CR36","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41577-021-00574-3","volume":"22","author":"M Philip","year":"2022","unstructured":"Philip, M. & Schietinger, A. CD8(+) T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. 22, 209\u2013223 (2022).","journal-title":"Nat. Rev. Immunol."},{"key":"50441_CR37","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1038\/s43018-020-00121-4","volume":"1","author":"NG Steele","year":"2020","unstructured":"Steele, N. G. et al. Multimodal mapping of the tumor and peripheral blood immune landscape in human pancreatic cancer. Nat. Cancer 1, 1097\u20131112 (2020).","journal-title":"Nat. Cancer"},{"key":"50441_CR38","doi-asserted-by":"publisher","first-page":"2330","DOI":"10.1158\/2159-8290.CD-21-1248","volume":"12","author":"A Schalck","year":"2022","unstructured":"Schalck, A. et al. Single-cell sequencing reveals trajectory of tumor-infiltrating lymphocyte states in pancreatic cancer. Cancer Discov. 12, 2330\u20132349 (2022).","journal-title":"Cancer Discov."},{"key":"50441_CR39","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/nature10600","volume":"479","author":"DJ Baker","year":"2011","unstructured":"Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232\u2013236 (2011).","journal-title":"Nature"},{"key":"50441_CR40","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nm.3048","volume":"19","author":"AJ Souers","year":"2013","unstructured":"Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202\u2013208 (2013).","journal-title":"Nat. Med."},{"key":"50441_CR41","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1158\/2326-6066.CIR-14-0215","volume":"3","author":"R Winograd","year":"2015","unstructured":"Winograd, R. et al. Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma. Cancer Immunol. Res. 3, 399\u2013411 (2015).","journal-title":"Cancer Immunol. Res."},{"key":"50441_CR42","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s43018-023-00526-x","volume":"4","author":"S Barthel","year":"2023","unstructured":"Barthel, S., Falcomata, C., Rad, R., Theis, F. J. & Saur, D. Single-cell profiling to explore pancreatic cancer heterogeneity, plasticity and response to therapy. Nat. Cancer 4, 454\u2013467 (2023).","journal-title":"Nat. Cancer"},{"key":"50441_CR43","doi-asserted-by":"crossref","unstructured":"Prieto, L. I. et al. Senescent alveolar macrophages promote early-stage lung tumorigenesis. Cancer Cell, 41, 1261\u20131275 (2023).","DOI":"10.1016\/j.ccell.2023.05.006"},{"key":"50441_CR44","doi-asserted-by":"crossref","unstructured":"Haston, S. et al. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer. Cancer Cell, 41, 1242\u20131260 (2023).","DOI":"10.1016\/j.ccell.2023.05.004"},{"key":"50441_CR45","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.ccell.2023.02.004","volume":"41","author":"N Bancaro","year":"2023","unstructured":"Bancaro, N. et al. Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer. Cancer Cell 41, 602\u2013619.e611 (2023).","journal-title":"Cancer Cell"},{"key":"50441_CR46","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1242\/dev.090159","volume":"140","author":"FC Pan","year":"2013","unstructured":"Pan, F. C. et al. Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140, 751\u2013764 (2013).","journal-title":"Development"},{"key":"50441_CR47","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/S1535-6108(04)00085-6","volume":"5","author":"DA Tuveson","year":"2004","unstructured":"Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375\u2013387 (2004).","journal-title":"Cancer Cell"},{"key":"50441_CR48","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1101\/gad.14.8.994","volume":"14","author":"S Marino","year":"2000","unstructured":"Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994\u20131004 (2000).","journal-title":"Genes Dev."},{"key":"50441_CR49","doi-asserted-by":"publisher","first-page":"40778","DOI":"10.18632\/oncotarget.17253","volume":"8","author":"T Golan","year":"2017","unstructured":"Golan, T. et al. Pancreatic cancer ascites xenograft-an expeditious model mirroring advanced therapeutic resistant disease. Oncotarget 8, 40778\u201340790 (2017).","journal-title":"Oncotarget"},{"key":"50441_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun. 10, 1523 (2019).","journal-title":"Nat. Commun."},{"key":"50441_CR51","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-50441-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-50441-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-50441-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T07:11:42Z","timestamp":1721632302000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-50441-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,22]]},"references-count":51,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["50441"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-50441-7","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,22]]},"assertion":[{"value":"6 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 July 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"B.Z.S. receives sponsored research support from Boehringer-Ingelheim and Revolution Medicines and holds equity in iTeos Therapeutics. T.G. Receives research support from Astra Zeneca, Abbvie honoraria, consultation fees from Abbvie and MSD Merck, royalties and consultant fees from Curesponse, and speaker fees from Abbvie and ClearNote Health. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6162"}}