{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:02:33Z","timestamp":1780315353316,"version":"3.54.1"},"reference-count":85,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2020.008.1"],"award-info":[{"award-number":["2020.008.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2020.008.1"],"award-info":[{"award-number":["2020.008.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2020.008.1"],"award-info":[{"award-number":["2020.008.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2020.008.1"],"award-info":[{"award-number":["2020.008.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["# 414985841, GRK 2566"],"award-info":[{"award-number":["# 414985841, GRK 2566"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["# 414985841, GRK 2566"],"award-info":[{"award-number":["# 414985841, GRK 2566"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["# 414985841, GRK 2566"],"award-info":[{"award-number":["# 414985841, GRK 2566"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sig Transduct Target Ther"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Breast cancer (BC) is the most common type of cancer among women worldwide and underlies relapse, disease progression, and metastasis. Resistance to chemotherapy and programmed cell death (PCD), including apoptosis, strongly affects BC therapy success and remains a major challenge. Although necroptosis, a lytic, and via damage-associated molecular patterns (DAMP) release, highly immunogenic mode of PCD, might overcome apoptosis resistance, there is an urgent need for physiological and translational human models to model necroptosis and PCD resistance in BC. Here, we apply 3D patient-derived, metastatic human mammary organoids (hMOs) to model apoptosis resistance, necroptosis, and inflammatory signaling using single-cell CITE-sequencing, time-lapse live cell brightfield, and immunofluorescent confocal microscopy, as well as biochemical approaches. Smac mimetic-triggered apoptosis could be confirmed in a panel of BC hMOs. Upon inducing apoptosis resistance with caspase inhibition, BC hMOs rapidly undergo necroptosis with profound MLKL phosphorylation. Necroptotic cell death was preceded by prominent transcriptional upregulation of inflammatory cyto- and chemokines, including interferons, that activate natural killer cells. Finally, necroptosis and the expression and release of inflammatory messengers in metastatic BC hMOs could be attenuated upon the inhibition of linear ubiquitination. We describe a novel experimental platform to model PCD, inflammation, and necroptosis that allows therapeutic screening to overcome chemotherapy resistance in patient-derived metastatic BC hMOs. With this platform, we identified necroptosis-induced interferon signaling, suggesting Smac mimetics and necroptosis as a potential immunotherapy strategy against metastatic BC.<\/jats:p>","DOI":"10.1038\/s41392-026-02755-9","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T10:07:00Z","timestamp":1780308420000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Necroptosis triggers inflammatory interferon signatures in patient-derived metastatic breast cancer organoids"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1697-124X","authenticated-orcid":false,"given":"Kaja Nicole","family":"W\u00e4chtersh\u00e4user","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana V.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alec","family":"Gessner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-9481","authenticated-orcid":false,"given":"Geoffroy","family":"Andrieux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan-Maximiliano","family":"Kur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Duschek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Weigert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3670-0602","authenticated-orcid":false,"given":"Melanie","family":"Boerries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4158-5872","authenticated-orcid":false,"given":"Michael A.","family":"Rieger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernst H. K.","family":"Stelzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4357-7320","authenticated-orcid":false,"given":"Francesco","family":"Pampaloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6532-7651","authenticated-orcid":false,"given":"Sjoerd J. L.","family":"van Wijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"2755_CR1","first-page":"10","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel, R. L., Kratzer, T. B., Giaquinto, A. N., Sung, H. & Jemal, A. Cancer statistics, 2025. CA Cancer J. Clin. 75, 10\u201345 (2025).","journal-title":"CA Cancer J. Clin."},{"key":"2755_CR2","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41392-024-02108-4","volume":"10","author":"X Xiong","year":"2025","unstructured":"Xiong, X. et al. Breast cancer: pathogenesis and treatments. Signal Transduct. Target. Ther. 10, 49 (2025).","journal-title":"Signal Transduct. Target. Ther."},{"key":"2755_CR3","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1038\/s41416-021-01564-x","volume":"126","author":"SK Herzog","year":"2021","unstructured":"Herzog, S. K. & Fuqua, S. A. W. ESR1 mutations and therapeutic resistance in metastatic breast cancer: progress and remaining challenges. Br. J. Cancer 126, 174\u2013186 (2021).","journal-title":"Br. J. Cancer"},{"key":"2755_CR4","doi-asserted-by":"publisher","first-page":"2101176","DOI":"10.1002\/advs.202101176","volume":"8","author":"P Chen","year":"2021","unstructured":"Chen, P. et al. Patient-derived organoids can guide personalized-therapies for patients with advanced breast cancer. Adv. Sci. 8, 2101176 (2021).","journal-title":"Adv. Sci."},{"key":"2755_CR5","doi-asserted-by":"publisher","first-page":"115803","DOI":"10.1016\/j.bcp.2023.115803","volume":"217","author":"YDT Tzeng","year":"2023","unstructured":"Tzeng, Y. D. T., Hsiao, J. H., Tseng, L. M., Hou, M. F. & Li, C. J. Breast cancer organoids derived from patients: A platform for tailored drug screening. Biochem. Pharmacol. 217, 115803 (2023).","journal-title":"Biochem. Pharmacol."},{"key":"2755_CR6","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.cell.2017.11.010","volume":"172","author":"N Sachs","year":"2018","unstructured":"Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373\u2013386 (2018).","journal-title":"Cell"},{"key":"2755_CR7","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1038\/s41596-020-00474-1","volume":"16","author":"JF Dekkers","year":"2021","unstructured":"Dekkers, J. F. et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat. Protoc. 16, 1936\u20131965 (2021).","journal-title":"Nat. Protoc."},{"key":"2755_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15548-7","volume":"11","author":"JM Rosenbluth","year":"2020","unstructured":"Rosenbluth, J. M. et al. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages. Nat. Commun. 11, 1711 (2020).","journal-title":"Nat. Commun."},{"key":"2755_CR9","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1016\/j.molmed.2017.02.007","volume":"23","author":"D Dutta","year":"2017","unstructured":"Dutta, D., Heo, I. & Clevers, H. Disease modeling in stem cell-derived 3D organoid systems. Trends Mol. Med. 23, 393\u2013410 (2017).","journal-title":"Trends Mol. Med."},{"key":"2755_CR10","doi-asserted-by":"publisher","first-page":"6194","DOI":"10.1126\/science.1247125","volume":"345","author":"MA Lancaster","year":"2014","unstructured":"Lancaster, M. A. & Knoblich, J. A. Organogenesisin a dish: Modeling development and disease using organoid technologies. Science 345, 6194 (2014).","journal-title":"Science"},{"key":"2755_CR11","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/s41568-018-0007-6","volume":"18","author":"J Drost","year":"2018","unstructured":"Drost, J. & Clevers, H. Organoids in cancer research. Nat. Rev. Cancer 18, 407\u2013418 (2018).","journal-title":"Nat. Rev. Cancer"},{"key":"2755_CR12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI175824","volume":"133","author":"PJH Zushin","year":"2023","unstructured":"Zushin, P. J. H., Mukherjee, S. & Wu, J. C. FDA Modernization Act 2.0: transitioning beyond animal models with human cells, organoids, and AI\/ML-based approaches. J. Clin. Invest. 133, e175824 (2023).","journal-title":"J. Clin. Invest."},{"key":"2755_CR13","doi-asserted-by":"publisher","first-page":"12046","DOI":"10.3390\/ijms241512046","volume":"24","author":"O Urz\u00ec","year":"2023","unstructured":"Urz\u00ec, O. et al. Three-dimensional cell cultures: the bridge between in vitro and in vivo models. Int. J. Mol. Sci. 24, 12046 (2023).","journal-title":"Int. J. Mol. Sci."},{"key":"2755_CR14","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.2147\/OTT.S33375","volume":"9","author":"L Dubrez","year":"2013","unstructured":"Dubrez, L., Berthelet, J. & Glorian, V. IAP proteins as targets for drug development in oncology. Onco. Targets Ther. 9, 1285\u20131304 (2013).","journal-title":"Onco. Targets Ther."},{"key":"2755_CR15","doi-asserted-by":"publisher","first-page":"785","DOI":"10.2174\/156800907783220471","volume":"7","author":"S Danson","year":"2007","unstructured":"Danson, S., Dean, E., Dive, C. & Ranson, M. IAPs as a target for anticancer therapy. Curr. Cancer Drug Targets 7, 785\u2013794 (2007).","journal-title":"Curr. Cancer Drug Targets"},{"key":"2755_CR16","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/nrm1621","volume":"6","author":"DL Vaux","year":"2005","unstructured":"Vaux, D. L. & Silke, J. IAPs, RINGs and ubiquitylation. Nat. Rev. Mol. Cell Biol. 6, 287\u2013297 (2005).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2755_CR17","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.71451","volume":"14","author":"MR Patel","year":"2025","unstructured":"Patel, M. R. et al. The second mitochondria-derived activator of Caspases Mimetic BI 891065 in patients with advanced solid tumors: results from two Phase I Studies. Cancer Med 14, e71451 (2025).","journal-title":"Cancer Med"},{"key":"2755_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2024.103651","volume":"9","author":"FR Liu","year":"2024","unstructured":"Liu, F. R. et al. Inhibitor of apoptosis proteins (IAP) inhibitor APG-1387 monotherapy or in combination with programmed cell death 1 (PD-1) inhibitor toripalimab in patients with advanced solid tumors: results from two phase I trials. ESMO Open 9, 103651 (2024).","journal-title":"ESMO Open"},{"key":"2755_CR19","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.molcel.2008.05.014","volume":"30","author":"MJM Bertrand","year":"2008","unstructured":"Bertrand, M. J. M. et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol. Cell 30, 689\u2013700 (2008).","journal-title":"Mol. Cell"},{"key":"2755_CR20","doi-asserted-by":"publisher","first-page":"11778","DOI":"10.1073\/pnas.0711122105","volume":"105","author":"DJ Mahoney","year":"2008","unstructured":"Mahoney, D. J. et al. Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc. Natl. Acad. Sci. Usa. 105, 11778\u201311783 (2008).","journal-title":"Proc. Natl. Acad. Sci. Usa."},{"key":"2755_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/cshperspect.a008656","volume":"5","author":"DR McIlwain","year":"2013","unstructured":"McIlwain, D. R., Berger, T. & Mak, T. W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. 5, 1\u201328 (2013).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2755_CR22","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0092-8674(03)00521-X","volume":"114","author":"O Micheau","year":"2003","unstructured":"Micheau, O. & Tschopp, J. Induction of TNF Receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181\u2013190 (2003).","journal-title":"Cell"},{"key":"2755_CR23","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.ccell.2025.12.005","volume":"44","author":"L Galluzzi","year":"2026","unstructured":"Galluzzi, L., Kepp, O., Zitvogel, L., Tang, D. & Kroemer, G. Cancer cell death: Cell-autonomous and immunogenic dimensions. Cancer Cell 44, 281\u2013305 (2026).","journal-title":"Cancer Cell"},{"key":"2755_CR24","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1016\/j.cell.2009.05.037","volume":"137","author":"YS Cho","year":"2009","unstructured":"Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112\u20131123 (2009).","journal-title":"Cell"},{"key":"2755_CR25","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.tibs.2024.11.006","volume":"50","author":"H Hoblos","year":"2025","unstructured":"Hoblos, H., Cawthorne, W., Samson, A. L. & Murphy, J. M. Protein shapeshifting in necroptotic cell death signaling. Trends Biochem. Sci. 50, 92\u2013105 (2025).","journal-title":"Trends Biochem. Sci."},{"key":"2755_CR26","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/s41419-024-06801-8","volume":"15","author":"AJ Rucker","year":"2024","unstructured":"Rucker, A. J., Park, C. S., Li, Q. J., Moseman, E. A. & Chan, F. K. M. Necroptosis stimulates interferon-mediated protective anti-tumor immunity. Cell Death Dis. 2024 15, 403 (2024).","journal-title":"Cell Death Dis. 2024"},{"key":"2755_CR27","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41418-020-00676-w","volume":"28","author":"AS Jahan","year":"2021","unstructured":"Jahan, A. S., Elb\u00e6k, C. R. & Damgaard, R. B. Met1-linked ubiquitin signalling in health and disease: inflammation, immunity, cancer, and beyond. Cell Death Differ. 28, 473\u2013492 (2021).","journal-title":"Cell Death Differ."},{"key":"2755_CR28","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nature09816","volume":"471","author":"B Gerlach","year":"2011","unstructured":"Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591\u2013596 (2011).","journal-title":"Nature"},{"key":"2755_CR29","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nature09814","volume":"471","author":"F Ikeda","year":"2011","unstructured":"Ikeda, F. et al. SHARPIN forms a linear ubiquitin ligase complex regulating NF-\u03baB activity and apoptosis. Nature 471, 637\u2013641 (2011).","journal-title":"Nature"},{"key":"2755_CR30","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/nature09815","volume":"471","author":"F Tokunaga","year":"2011","unstructured":"Tokunaga, F. et al. SHARPIN is a component of the NF-\u03baB-activating linear ubiquitin chain assembly complex. Nature 471, 633\u2013636 (2011).","journal-title":"Nature"},{"key":"2755_CR31","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1007\/s10875-025-01939-2","volume":"45","author":"L Wang","year":"2025","unstructured":"Wang, L., Xiao, J., Gan, R., Tang, X. & Wu, J. Novel compound heterozygous mutations in HOIP result in autoinflammation and immunodeficiency. J. Clin. Immunol. 45, 135 (2025).","journal-title":"J. Clin. Immunol."},{"key":"2755_CR32","doi-asserted-by":"publisher","first-page":"167355","DOI":"10.1016\/j.bbadis.2024.167355","volume":"1870","author":"M Wang","year":"2024","unstructured":"Wang, M. et al. A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death. Biochim. Biophys. Acta Mol. Basis Dis. 1870, 167355 (2024).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"2755_CR33","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1038\/s41590-024-01817-w","volume":"25","author":"H Oda","year":"2024","unstructured":"Oda, H. et al. Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency. Nat. Immunol. 25, 764\u2013777 (2024).","journal-title":"Nat. Immunol."},{"key":"2755_CR34","doi-asserted-by":"publisher","first-page":"479","DOI":"10.3389\/fimmu.2019.00479","volume":"10","author":"H Oda","year":"2019","unstructured":"Oda, H. et al. Second case of HOIP deficiency expands clinical features and defines inflammatory transcriptome regulated by LUBAC. Front. Immunol. 10, 479 (2019).","journal-title":"Front. Immunol."},{"key":"2755_CR35","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1084\/jem.20141130","volume":"212","author":"B Boisson","year":"2015","unstructured":"Boisson, B. et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J. Exp. Med. 212, 939\u2013951 (2015).","journal-title":"J. Exp. Med."},{"key":"2755_CR36","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1038\/ni.2457","volume":"13","author":"B Boisson","year":"2012","unstructured":"Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13, 1178\u20131186 (2012).","journal-title":"Nat. Immunol."},{"key":"2755_CR37","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.bbrc.2018.12.164","volume":"509","author":"K Katsuya","year":"2019","unstructured":"Katsuya, K. et al. Small-molecule inhibitors of linear ubiquitin chain assembly complex (LUBAC), HOIPINs, suppress NF-\u03baB signaling. Biochem. Biophys. Res. Commun. 509, 700\u2013706 (2019).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2755_CR38","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-024-06447-6","volume":"15","author":"N Weinelt","year":"2024","unstructured":"Weinelt, N. et al. LUBAC-mediated M1 Ub regulates necroptosis by segregating the cellular distribution of active MLKL. Cell Death Dis. 15, 77 (2024).","journal-title":"Cell Death Dis."},{"key":"2755_CR39","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1038\/s43018-021-00229-1","volume":"2","author":"N Pasha","year":"2021","unstructured":"Pasha, N. & Turner, N. C. Understanding and overcoming tumor heterogeneity in metastatic breast cancer treatment. Nat. Cancer 2, 680\u2013692 (2021).","journal-title":"Nat. Cancer"},{"key":"2755_CR40","doi-asserted-by":"publisher","first-page":"2820","DOI":"10.1158\/0008-5472.CAN-23-3082","volume":"84","author":"G Lee","year":"2024","unstructured":"Lee, G. et al. E-Cadherin induces serine synthesis to support progression and metastasis of breast cancer. Cancer Res. 84, 2820\u20132835 (2024).","journal-title":"Cancer Res"},{"key":"2755_CR41","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1038\/s41388-024-03007-2","volume":"43","author":"GC Russo","year":"2024","unstructured":"Russo, G. C. et al. E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer. Oncogene 43, 1445\u20131462 (2024).","journal-title":"Oncogene"},{"key":"2755_CR42","doi-asserted-by":"publisher","first-page":"163","DOI":"10.3727\/105221615X14399878166113","volume":"16","author":"M Takaku","year":"2015","unstructured":"Takaku, M., Grimm, S. A. & Wade, P. A. GATA3 in breast cancer: tumor suppressor or oncogene? Gene Expr. 16, 163\u2013168 (2015).","journal-title":"Gene Expr."},{"key":"2755_CR43","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1158\/1055-9965.EPI-06-1090","volume":"17","author":"D Voduc","year":"2008","unstructured":"Voduc, D., Cheang, M. & Nielsen, T. GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol. Biomark. Prev. 17, 365\u2013373 (2008).","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"2755_CR44","doi-asserted-by":"publisher","first-page":"142","DOI":"10.4048\/jbc.2017.20.2.142","volume":"20","author":"F Ye","year":"2017","unstructured":"Ye, F. et al. CD49f can act as a biomarker for local or distant recurrence in breast cancer. J. Breast Cancer 20, 142\u2013149 (2017).","journal-title":"J. Breast Cancer"},{"key":"2755_CR45","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"},{"key":"2755_CR46","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/ng1180","volume":"34","author":"VK Mootha","year":"2003","unstructured":"Mootha, V. K. et al. PGC-1\u03b1-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267\u2013273 (2003).","journal-title":"Nat. Genet."},{"key":"2755_CR47","doi-asserted-by":"publisher","first-page":"1370800","DOI":"10.3389\/fimmu.2024.1370800","volume":"15","author":"S Zhi","year":"2024","unstructured":"Zhi, S. et al. Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment. Front. Immunol. 15, 1370800 (2024).","journal-title":"Front. Immunol."},{"key":"2755_CR48","first-page":"383","volume":"7","author":"SH Hare","year":"2017","unstructured":"Hare, S. H. & Harvey, A. J. mTOR function and therapeutic targeting in breast cancer. Am. J. Cancer Res. 7, 383\u2013404 (2017).","journal-title":"Am. J. Cancer Res."},{"key":"2755_CR49","doi-asserted-by":"publisher","first-page":"6462","DOI":"10.1038\/onc.2008.312","volume":"27","author":"B Hoffman","year":"2008","unstructured":"Hoffman, B. & Liebermann, D. A. Apoptotic signaling by c-MYC. Oncogene 27, 6462\u20136472 (2008).","journal-title":"Oncogene"},{"key":"2755_CR50","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1158\/1535-7163.MCT-15-0475","volume":"14","author":"RK Amaravadi","year":"2015","unstructured":"Amaravadi, R. K. et al. A Phase I study of the SMAC-mimetic birinapant in adults with refractory solid tumors or lymphoma. Mol. Cancer Ther. 14, 2569\u20132575 (2015).","journal-title":"Mol. Cancer Ther."},{"key":"2755_CR51","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1002\/cncr.29783","volume":"122","author":"AM Noonan","year":"2016","unstructured":"Noonan, A. M. et al. Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer. Cancer 122, 588\u2013597 (2016).","journal-title":"Cancer"},{"key":"2755_CR52","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.cell.2011.11.031","volume":"148","author":"L Sun","year":"2012","unstructured":"Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213\u2013227 (2012).","journal-title":"Cell"},{"key":"2755_CR53","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.molcel.2014.03.003","volume":"54","author":"H Wang","year":"2014","unstructured":"Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133\u2013146 (2014).","journal-title":"Mol. Cell"},{"key":"2755_CR54","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.abb.2016.01.017","volume":"593","author":"G Ferguson","year":"2016","unstructured":"Ferguson, G. & Bridge, W. Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of \u03b3-glutamylcysteine. Arch. Biochem. Biophys. 593, 12\u201323 (2016).","journal-title":"Arch. Biochem. Biophys."},{"key":"2755_CR55","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1186\/s13287-021-02654-6","volume":"12","author":"HHT Le","year":"2021","unstructured":"Le, H. H. T. et al. Genome-wide differential expression profiling of lncRNAs and mRNAs in human induced pluripotent stem cell-derived endothelial cells exposed to e-cigarette extract. Stem Cell Res. Ther. 12, 593 (2021).","journal-title":"Stem Cell Res. Ther."},{"key":"2755_CR56","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/S0167-5699(00)01673-X","volume":"21","author":"L Moretta","year":"2000","unstructured":"Moretta, L., Biassoni, R., Bottino, C., Mingari, M. C. & Moretta, A. Human NK-cell receptors. Immunol. Today 21, 420\u2013422 (2000).","journal-title":"Immunol. Today"},{"key":"2755_CR57","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.molimm.2004.07.034","volume":"42","author":"MJ Smyth","year":"2005","unstructured":"Smyth, M. J. et al. Activation of NK cell cytotoxicity. Mol. Immunol. 42, 501\u2013510 (2005).","journal-title":"Mol. Immunol."},{"key":"2755_CR58","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.3390\/biomedicines11041058","volume":"11","author":"EM Tosca","year":"2023","unstructured":"Tosca, E. M., Ronchi, D., Facciolo, D. & Magni, P. Replacement, reduction, and refinement of animal experiments in anticancer drug development: the contribution of 3D In vitro cancer models in the drug efficacy assessment. Biomedicines 11, 1058 (2023).","journal-title":"Biomedicines"},{"key":"2755_CR59","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s13287-020-1585-2","volume":"11","author":"M Dossena","year":"2020","unstructured":"Dossena, M. et al. Standardized GMP-compliant scalable production of human pancreas organoids. Stem Cell Res. Ther. 11, 94 (2020).","journal-title":"Stem Cell Res. Ther."},{"key":"2755_CR60","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1167\/tvst.10.10.9","volume":"10","author":"H Cobb","year":"2021","unstructured":"Cobb, H., Aparicio-Domingo, S. & Canto-Soler, M. V. Transitioning into GMP-compliance: alternative methods for producing retinal organoids for transplantation. Transl. Vis. Sci. Technol. 10, 10 (2021).","journal-title":"Transl. Vis. Sci. Technol."},{"key":"2755_CR61","doi-asserted-by":"publisher","first-page":"3869","DOI":"10.3390\/cancers12123869","volume":"12","author":"E Campaner","year":"2020","unstructured":"Campaner, E. et al. Breast cancer organoids model patient-specific response to drug treatment. Cancers 12, 3869 (2020).","journal-title":"Cancers"},{"key":"2755_CR62","doi-asserted-by":"publisher","first-page":"3602","DOI":"10.3390\/cancers15143602","volume":"15","author":"CE \u00d6nder","year":"2023","unstructured":"\u00d6nder, C. E. et al. Advancing cancer therapy predictions with patient-derived organoid models of metastatic breast cancer. Cancers 15, 3602 (2023).","journal-title":"Cancers"},{"key":"2755_CR63","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/s43018-022-00337-6","volume":"3","author":"KP Guillen","year":"2022","unstructured":"Guillen, K. P. et al. A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology. Nat. Cancer 3, 232\u2013250 (2022).","journal-title":"Nat. Cancer"},{"key":"2755_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-37012-4","volume":"13","author":"X Meng","year":"2023","unstructured":"Meng, X. et al. Association of quantitative analysis of intratumoral reduced E-cadherin expression with lymph node metastasis and prognosis in patients with breast cancer. Sci. Rep. 13, 10434 (2023).","journal-title":"Sci. Rep."},{"key":"2755_CR65","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/s41586-019-1526-3","volume":"573","author":"V Padmanaban","year":"2019","unstructured":"Padmanaban, V. et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573, 439\u2013444 (2019).","journal-title":"Nature"},{"key":"2755_CR66","doi-asserted-by":"publisher","first-page":"43363","DOI":"10.18632\/oncotarget.9715","volume":"7","author":"K Palen","year":"2016","unstructured":"Palen, K. et al. E-cadherin re-expression shows in vivo evidence for mesenchymal to epithelial transition in clonal metastatic breast tumor cells. Oncotarget 7, 43363\u201343375 (2016).","journal-title":"Oncotarget"},{"key":"2755_CR67","doi-asserted-by":"publisher","first-page":"5931","DOI":"10.1073\/pnas.1918167117","volume":"117","author":"TY Na","year":"2020","unstructured":"Na, T. Y., Schecterson, L., Mendonsa, A. M. & Gumbiner, B. M. The functional activity of E-cadherin controls tumor cell metastasis at multiple steps. Proc. Natl. Acad. Sci. USA 117, 5931\u20135937 (2020).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2755_CR68","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.cell.2007.10.030","volume":"131","author":"E Varfolomeev","year":"2007","unstructured":"Varfolomeev, E. et al. IAP antagonists induce Autoubiquitination of c-IAPs, NF-\u03baB activation, and TNF\u03b1-Dependent Apoptosis. Cell 131, 669\u2013681 (2007).","journal-title":"Cell"},{"key":"2755_CR69","doi-asserted-by":"publisher","first-page":"3634825","DOI":"10.1155\/2020\/3634825","volume":"2020","author":"AK Verma","year":"2020","unstructured":"Verma, A. K. et al. Expression and correlation of cell-free cIAP-1 and cIAP-2 mRNA in breast cancer patients: a study from India. J. Oncol. 2020, 3634825 (2020).","journal-title":"J. Oncol."},{"key":"2755_CR70","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-017-3627-4","volume":"17","author":"AR Hussain","year":"2017","unstructured":"Hussain, A. R. et al. XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis. BMC Cancer 17, 604 (2017).","journal-title":"BMC Cancer"},{"key":"2755_CR71","doi-asserted-by":"publisher","first-page":"335","DOI":"10.3390\/app11010335","volume":"11","author":"YC Chang","year":"2020","unstructured":"Chang, Y. C. & Cheung, C. H. A. An updated review of Smac Mimetics, LCL161, Birinapant, and GDC-0152 in cancer treatment. Appl. Sci. 11, 335 (2020).","journal-title":"Appl. Sci."},{"key":"2755_CR72","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1007\/s10549-012-2352-6","volume":"137","author":"JL Allensworth","year":"2012","unstructured":"Allensworth, J. L., Sauer, S. J., Lyerly, H. K., Morse, M. A. & Devi, G. R. Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-\u03b1-independent mechanism. Breast Cancer Res. Treat. 137, 359\u2013371 (2012).","journal-title":"Breast Cancer Res. Treat."},{"key":"2755_CR73","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1126\/scisignal.3123pe18","volume":"3","author":"SC Sun","year":"2010","unstructured":"Sun, S. C. Controlling the fate of NIK: a central stage in noncanonical NF-\u03baB signaling. Sci. Signal. 3, 18 (2010).","journal-title":"Sci. Signal."},{"key":"2755_CR74","doi-asserted-by":"publisher","first-page":"30680","DOI":"10.1074\/jbc.M114.587808","volume":"289","author":"S Lee","year":"2014","unstructured":"Lee, S., Challa-Malladi, M., Bratton, S. B. & Wright, C. W. Nuclear factor-\u03baB-inducing kinase (NIK) contains an amino-terminal inhibitor of apoptosis (IAP)-binding motif (IBM) that potentiates NIK degradation by cellular IAP1 (c-IAP1). J. Biol. Chem. 289, 30680\u201330689 (2014).","journal-title":"J. Biol. Chem."},{"key":"2755_CR75","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41568-024-00674-x","volume":"24","author":"P Meier","year":"2024","unstructured":"Meier, P., Legrand, A. J., Adam, D. & Silke, J. Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity. Nat. Rev. Cancer 24, 299\u2013315 (2024).","journal-title":"Nat. Rev. Cancer"},{"key":"2755_CR76","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1111\/1440-1681.13711","volume":"49","author":"B Thakur","year":"2022","unstructured":"Thakur, B., Saha, L. & Bhatia, A. Relative refractoriness of breast cancer cells to tumour necrosis factor-\u03b1 induced necroptosis. Clin. Exp. Pharmacol. Physiol. 49, 1294\u20131306 (2022).","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"2755_CR77","doi-asserted-by":"publisher","first-page":"106700","DOI":"10.1016\/j.intimp.2020.106700","volume":"86","author":"S Tang","year":"2020","unstructured":"Tang, S., Ning, Q., Yang, L., Mo, Z. & Tang, S. Mechanisms of immune escape in the cancer immune cycle. Int. Immunopharmacol. 86, 106700 (2020).","journal-title":"Int. Immunopharmacol."},{"key":"2755_CR78","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-024-01887-6","volume":"26","author":"Y Zhang","year":"2024","unstructured":"Zhang, Y., Zhong, F. & Liu, L. Single-cell transcriptional atlas of tumor-associated macrophages in breast cancer. Breast Cancer Res. 26, 129 (2024).","journal-title":"Breast Cancer Res"},{"key":"2755_CR79","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1016\/j.celrep.2018.07.060","volume":"24","author":"CD Geary","year":"2018","unstructured":"Geary, C. D. et al. Non-redundant ISGF3 components promote NK cell survival in an auto-regulatory manner during viral infection. Cell Rep. 24, 1949\u20131957 (2018).","journal-title":"Cell Rep."},{"key":"2755_CR80","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-13-134","volume":"13","author":"J Ye","year":"2012","unstructured":"Ye, J. et al. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinforma. 13, 134 (2012).","journal-title":"BMC Bioinforma."},{"key":"2755_CR81","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1038\/nmeth.4380","volume":"14","author":"M Stoeckius","year":"2017","unstructured":"Stoeckius, M. et al. Simultaneous epitope and transcriptome measurement in single cells. Nat. Methods 14, 865\u2013868 (2017).","journal-title":"Nat. Methods"},{"key":"2755_CR82","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","volume":"42","author":"Y Hao","year":"2023","unstructured":"Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293\u2013304 (2023).","journal-title":"Nat. Biotechnol."},{"key":"2755_CR83","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","volume":"27","author":"A Liberzon","year":"2011","unstructured":"Liberzon, A. et al. Molecular signatures database (MSigDB) 3.0. Bioinformatics 27, 1739\u20131740 (2011).","journal-title":"Bioinformatics"},{"key":"2755_CR84","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","volume":"1","author":"A Liberzon","year":"2015","unstructured":"Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417\u2013425 (2015).","journal-title":"Cell Syst."},{"key":"2755_CR85","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1200\/JCO.2008.18.1370","volume":"27","author":"JS Parker","year":"2009","unstructured":"Parker, J. S. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27, 1160\u20131167 (2009).","journal-title":"J. Clin. Oncol."}],"container-title":["Signal Transduction and Targeted Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02755-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02755-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02755-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T11:03:14Z","timestamp":1780311794000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41392-026-02755-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":85,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2755"],"URL":"https:\/\/doi.org\/10.1038\/s41392-026-02755-9","relation":{},"ISSN":["2059-3635"],"issn-type":[{"value":"2059-3635","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"assertion":[{"value":"15 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"204"}}