{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T07:40:01Z","timestamp":1751614801346,"version":"3.41.0"},"posted":{"date-parts":[[2025,2,6]]},"group-title":"In Review","reference-count":32,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,10]]},"abstract":"<title>Abstract<\/title>\n        <p>Despite initial efficacy of radiotherapy (RT), with or without concurrent androgen-deprivation, in prostate adenocarcinoma (PCa), neuroendocrine prostate cancer (NEPC) emerging from disease progression is a highly aggressive malignancy for which standard therapies are mostly ineffective. Although oncogenic <italic>MUC1-C<\/italic> is a leading driver of NEPC and of PCa lineage plasticity, its putative role in response to RT, including RT-induced neuroendocrine transdifferentiation (tNED), has not been explored. We thus aimed to explore the interplay between androgen receptor (AR) signaling and MUC1 in PCa progression to NEPC. Firstly, using a radioresistant PCa cell line (22Rv1-RR) we demonstrated that epigenetic suppression of AR signaling caused MUC1\/MUC1-C upregulation, which seems to be activated through \u03b3STAT3. MUC1 activation positively associated with increased expression of neuroendocrine-related markers, including CD56, chromogranin A, synaptophysin and INSM transcriptional repressor 1 (INSM1). In NEPC tissues and comparing to prostate adenocarcinoma, MUC1 was upregulated and negatively correlated with AR, which was suppressed. Finally, proteomic analyses revealed that MUC1 activation upon RT selective pressure led to acquisition of stemness features, induction of epithelial to mesenchymal transition, and enhancement of basal cell-like traits. Notably, MUC1 knockdown (KD) significantly boosted response to RT in both 22Rv1-RR and DU145 cell lines. Moreover, AR-induced overexpression in PC3 cell lines entailed MUC1 downregulation, resulting in attenuated neuroendocrine (NE) traits and radioresistance, as well as impaired cell migration and invasion capabilities. Collectively, these results highlight MUC1 as a promising radiosensitization target and may ultimately help overcome therapy resistance and NEPC progression.<\/p>","DOI":"10.21203\/rs.3.rs-5614729\/v1","type":"posted-content","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T13:17:33Z","timestamp":1738847853000},"source":"Crossref","is-referenced-by-count":0,"title":["Decoding MUC1 and AR axis in a radiation-induced neuroendocrine prostate cancer cell-subpopulation unveils novel therapeutic targets"],"prefix":"10.21203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"first","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC)"}]},{"given":"Catarina","family":"Macedo-Silva","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (CI-IPOP)"}]},{"given":"\u00c2ngela","family":"Castro","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC)"}]},{"given":"Iris","family":"Carri\u00e7o","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC)"}]},{"given":"Joana Lencart","family":"Lencart","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC)"}]},{"given":"Isa","family":"Carneiro","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC)"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7312-5387","authenticated-orcid":false,"given":"lucia","family":"altucci","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli studi della Campania Luigi Vanvitelli"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6829-1391","authenticated-orcid":false,"given":"Joao","family":"Lobo","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto"}]},{"given":"Vera","family":"Miranda-Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO Porto)"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO Porto)"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4378-0820","authenticated-orcid":false,"given":"Margareta","family":"Correia","sequence":"additional","affiliation":[{"name":"Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center Raquel Seruca (Porto.CCC)"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"778758","DOI":"10.3389\/fendo.2021.778758","article-title":"Neuroendocrine Carcinoma as an Independent Prognostic Factor for Patients With Prostate Cancer: A Population-Based Study","volume":"12","author":"Yao J","year":"2021","unstructured":"Yao J, Liu Y, Liang X, Shao J, Zhang Y, Yang J, et al. Neuroendocrine Carcinoma as an Independent Prognostic Factor for Patients With Prostate Cancer: A Population-Based Study. Front Endocrinol (Lausanne). 2021;12:778758.","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ejca.2019.08.011","article-title":"Clinical features of neuroendocrine prostate cancer","volume":"121","author":"Conteduca V","year":"2019","unstructured":"Conteduca V, Oromendia C, Eng KW, Bareja R, Sigouros M, Molina A, et al. Clinical features of neuroendocrine prostate cancer. Eur J Cancer. 2019;121:7\u201318.","journal-title":"Eur J Cancer"},{"issue":"10","key":"ref3","doi-asserted-by":"crossref","DOI":"10.3390\/cancers11101405","article-title":"Neuroendocrine Differentiation of Prostate Cancer-An Intriguing Example of Tumor Evolution at Play","volume":"11","author":"Patel GK","year":"2019","unstructured":"Patel GK, Chugh N, Tripathi M. Neuroendocrine Differentiation of Prostate Cancer-An Intriguing Example of Tumor Evolution at Play. Cancers (Basel). 2019;11(10).","journal-title":"Cancers (Basel)"},{"key":"ref4","first-page":"90","article-title":"Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure","volume":"5","author":"Hu CD","year":"2015","unstructured":"Hu CD, Choo R, Huang J. Neuroendocrine differentiation in prostate cancer: a mechanism of radioresistance and treatment failure. Front Oncol. 2015;5:90.","journal-title":"Front Oncol"},{"issue":"7","key":"ref5","first-page":"834","article-title":"Ionizing radiation induces neuroendocrine differentiation of prostate cancer cells in vitro, in vivo and in prostate cancer patients","volume":"1","author":"Deng X","year":"2011","unstructured":"Deng X, Elzey BD, Poulson JM, Morrison WB, Ko SC, Hahn NM, et al. Ionizing radiation induces neuroendocrine differentiation of prostate cancer cells in vitro, in vivo and in prostate cancer patients. Am J Cancer Res. 2011;1(7):834\u201344.","journal-title":"Am J Cancer Res"},{"issue":"2","key":"ref6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.bbcan.2018.06.006","article-title":"EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers","volume":"1870","author":"Soundararajan R","year":"2018","unstructured":"Soundararajan R, Paranjape AN, Maity S, Aparicio A, Mani SA. EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers. Biochim Biophys Acta Rev Cancer. 2018;1870(2):229\u201338.","journal-title":"Biochim Biophys Acta Rev Cancer"},{"issue":"13","key":"ref7","doi-asserted-by":"crossref","DOI":"10.3390\/cancers15133363","article-title":"Neoadjuvant versus Concurrent Androgen Deprivation Therapy in Localized Prostate Cancer Treated with Radiotherapy: A Systematic Review of the Literature","volume":"15","author":"Cartes R","year":"2023","unstructured":"Cartes R, Karim MU, Tisseverasinghe S, Tolba M, Bahoric B, Anidjar M, et al. Neoadjuvant versus Concurrent Androgen Deprivation Therapy in Localized Prostate Cancer Treated with Radiotherapy: A Systematic Review of the Literature. Cancers (Basel). 2023;15(13).","journal-title":"Cancers (Basel)"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"865350","DOI":"10.3389\/fonc.2022.865350","article-title":"Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective","volume":"12","author":"Huang J","year":"2022","unstructured":"Huang J, Lin B, Li B. Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective. Front Oncol. 2022;12:865350.","journal-title":"Front Oncol"},{"issue":"3","key":"ref9","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.eururo.2014.09.049","article-title":"Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level","volume":"67","author":"Karantanos T","year":"2015","unstructured":"Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. 2015;67(3):470\u20139.","journal-title":"Eur Urol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2021.06.006","article-title":"Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance","volume":"518","author":"Jamroze A","year":"2021","unstructured":"Jamroze A, Chatta G, Tang DG. Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance. Cancer Lett. 2021;518:1\u20139.","journal-title":"Cancer Lett"},{"issue":"10","key":"ref11","doi-asserted-by":"crossref","DOI":"10.3390\/biom13101526","article-title":"Novel Insights on the Role of Epigenetics in Androgen Receptor's Expression in Prostate Cancer","volume":"13","author":"Camilo V","year":"2023","unstructured":"Camilo V, Pacheco MB, Moreira-Silva F, Outeiro-Pinho G, Gaspar VM, Mano JF, et al. Novel Insights on the Role of Epigenetics in Androgen Receptor's Expression in Prostate Cancer. Biomolecules. 2023;13(10).","journal-title":"Biomolecules"},{"issue":"1","key":"ref12","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41467-019-14219-6","article-title":"MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer","volume":"11","author":"Yasumizu Y","year":"2020","unstructured":"Yasumizu Y, Rajabi H, Jin C, Hata T, Pitroda S, Long MD, et al. MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer. Nat Commun. 2020;11(1):338.","journal-title":"Nat Commun"},{"issue":"3","key":"ref13","doi-asserted-by":"crossref","first-page":"811","DOI":"10.7150\/ijbs.79928","article-title":"Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy","volume":"19","author":"Yu Y","year":"2023","unstructured":"Yu Y, Yu J, Ge S, Su Y, Fan X. Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy. Int J Biol Sci. 2023;19(3):811\u201328.","journal-title":"Int J Biol Sci"},{"issue":"1","key":"ref14","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1080\/21655979.2020.1791590","article-title":"MUC1 confers radioresistance in head and neck squamous cell carcinoma (HNSCC) cells","volume":"11","author":"Huang TQ","year":"2020","unstructured":"Huang TQ, Bi YN, Cui Z, Guan JP, Huang YC. MUC1 confers radioresistance in head and neck squamous cell carcinoma (HNSCC) cells. Bioengineered. 2020;11(1):769\u201378.","journal-title":"Bioengineered"},{"issue":"6","key":"ref15","first-page":"7571","article-title":"Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2\/STAT3 signaling","volume":"14","author":"Yi FT","year":"2017","unstructured":"Yi FT, Lu QP. Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2\/STAT3 signaling. Oncol Lett. 2017;14(6):7571\u20136.","journal-title":"Oncol Lett"},{"issue":"12","key":"ref16","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1038\/sj.bjc.6602232","article-title":"MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by 213Bi-C595 radioimmunoconjugate","volume":"91","author":"Qu CF","year":"2004","unstructured":"Qu CF, Li Y, Song YJ, Rizvi SMA, Raja C, Zhang D, et al. MUC1 expression in primary and metastatic pancreatic cancer cells for in vitro treatment by 213Bi-C595 radioimmunoconjugate. British Journal of Cancer. 2004;91(12):2086\u201393.","journal-title":"British Journal of Cancer"},{"issue":"1","key":"ref17","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41392-023-01639-6","article-title":"Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling","volume":"8","author":"Macedo-Silva C","year":"2023","unstructured":"Macedo-Silva C, Miranda-Gon\u00e7alves V, Tavares NT, Barros-Silva D, Lencart J, Lobo J, et al. Epigenetic regulation of TP53 is involved in prostate cancer radioresistance and DNA damage response signaling. Signal Transduct Target Ther. 2023;8(1):395.","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"ref18","doi-asserted-by":"crossref","first-page":"2571","DOI":"10.1038\/s41467-019-09784-9","article-title":"LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2\/STAT3 signaling","volume":"10","author":"Luo J","year":"2019","unstructured":"Luo J, Wang K, Yeh S, Sun Y, Liang L, Xiao Y, et al. LncRNA-p21 alters the antiandrogen enzalutamide-induced prostate cancer neuroendocrine differentiation via modulating the EZH2\/STAT3 signaling. Nat Commun. 2019;10(1):2571.","journal-title":"Nat Commun"},{"issue":"23","key":"ref19","doi-asserted-by":"crossref","first-page":"9663","DOI":"10.1158\/0008-5472.CAN-08-2229","article-title":"Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression","volume":"68","author":"Deng X","year":"2008","unstructured":"Deng X, Liu H, Huang J, Cheng L, Keller ET, Parsons SJ, et al. Ionizing radiation induces prostate cancer neuroendocrine differentiation through interplay of CREB and ATF2: implications for disease progression. Cancer Res. 2008;68(23):9663\u201370.","journal-title":"Cancer Res"},{"issue":"2","key":"ref20","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/his.14707","article-title":"Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series","volume":"81","author":"Gopalan A","year":"2022","unstructured":"Gopalan A, Al-Ahmadie H, Chen YB, Sarungbam J, Sirintrapun SJ, Tickoo SK, et al. Neuroendocrine differentiation in the setting of prostatic carcinoma: contemporary assessment of a consecutive series. Histopathology. 2022;81(2):246\u201354.","journal-title":"Histopathology"},{"issue":"3","key":"ref21","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.ecl.2011.05.012","article-title":"Overview of prostate anatomy, histology, and pathology","volume":"40","author":"Lee CH","year":"2011","unstructured":"Lee CH, Akin-Olugbade O, Kirschenbaum A. Overview of prostate anatomy, histology, and pathology. Endocrinol Metab Clin North Am. 2011;40(3):565\u201375, viii-ix.","journal-title":"Endocrinol Metab Clin North Am"},{"issue":"4","key":"ref22","doi-asserted-by":"crossref","first-page":"215","DOI":"10.5114\/jcb.2013.39210","article-title":"Time to failure after definitive therapy for prostate cancer: implications for importance of aggressive local treatment","volume":"5","author":"Taira AV","year":"2013","unstructured":"Taira AV, Merrick GS, Butler WM, Galbreath RW, Fiano R, Wallner KE, et al. Time to failure after definitive therapy for prostate cancer: implications for importance of aggressive local treatment. J Contemp Brachytherapy. 2013;5(4):215\u201321.","journal-title":"J Contemp Brachytherapy"},{"issue":"2","key":"ref23","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1002\/cncr.23161","article-title":"Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes","volume":"112","author":"Agarwal PK","year":"2008","unstructured":"Agarwal PK, Sadetsky N, Konety BR, Resnick MI, Carroll PR. Treatment failure after primary and salvage therapy for prostate cancer: likelihood, patterns of care, and outcomes. Cancer. 2008;112(2):307\u201314.","journal-title":"Cancer"},{"issue":"3","key":"ref24","doi-asserted-by":"crossref","first-page":"288","DOI":"10.5534\/wjmh.180040","article-title":"Role of Androgen Receptor in Prostate Cancer: A Review","volume":"37","author":"Fujita K","year":"2019","unstructured":"Fujita K, Nonomura N. Role of Androgen Receptor in Prostate Cancer: A Review. World J Mens Health. 2019;37(3):288\u201395.","journal-title":"World J Mens Health"},{"issue":"2","key":"ref25","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1210\/er.2002-0032","article-title":"Androgen receptor in prostate cancer","volume":"25","author":"Heinlein CA","year":"2004","unstructured":"Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25(2):276\u2013308.","journal-title":"Endocr Rev"},{"issue":"16","key":"ref26","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1002\/pros.20654","article-title":"Human prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin A","volume":"67","author":"Leiblich A","year":"2007","unstructured":"Leiblich A, Cross SS, Catto JW, Pesce G, Hamdy FC, Rehman I. Human prostate cancer cells express neuroendocrine cell markers PGP 9.5 and chromogranin A. Prostate. 2007;67(16):1761\u20139.","journal-title":"Prostate"},{"issue":"1","key":"ref27","doi-asserted-by":"crossref","first-page":"3178","DOI":"10.1038\/s41598-024-53549-4","article-title":"Molecular crosstalk between MUC1 and STAT3 influences the anti-proliferative effect of Napabucasin in epithelial cancers","volume":"14","author":"Bose M","year":"2024","unstructured":"Bose M, Sanders A, Handa A, Vora A, Cardona MR, Brouwer C, et al. Molecular crosstalk between MUC1 and STAT3 influences the anti-proliferative effect of Napabucasin in epithelial cancers. Scientific Reports. 2024;14(1):3178.","journal-title":"Scientific Reports"},{"issue":"160","key":"ref28","doi-asserted-by":"crossref","first-page":"ra9","DOI":"10.1126\/scisignal.2001426","article-title":"MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop","volume":"4","author":"Ahmad R","year":"2011","unstructured":"Ahmad R, Rajabi H, Kosugi M, Joshi MD, Alam M, Vasir B, et al. MUC1-C oncoprotein promotes STAT3 activation in an autoinductive regulatory loop. Sci Signal. 2011;4(160):ra9.","journal-title":"Sci Signal"},{"issue":"2","key":"ref29","first-page":"337","article-title":"MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion","volume":"35","author":"Gao J","year":"2009","unstructured":"Gao J, McConnell MJ, Yu B, Li J, Balko JM, Black EP, et al. MUC1 is a downstream target of STAT3 and regulates lung cancer cell survival and invasion. Int J Oncol. 2009;35(2):337\u201345.","journal-title":"Int J Oncol"},{"issue":"1","key":"ref30","doi-asserted-by":"crossref","first-page":"100899","DOI":"10.1016\/j.tranon.2020.100899","article-title":"Plasticity of cancer cell invasion: Patterns and mechanisms","volume":"14","author":"Wu JS","year":"2021","unstructured":"Wu JS, Jiang J, Chen BJ, Wang K, Tang YL, Liang XH. Plasticity of cancer cell invasion: Patterns and mechanisms. Transl Oncol. 2021;14(1):100899.","journal-title":"Transl Oncol"},{"issue":"47","key":"ref31","doi-asserted-by":"crossref","first-page":"14406","DOI":"10.1073\/pnas.1519151112","article-title":"Advanced neuroendocrine prostate tumors regress to stemness","volume":"112","author":"Ellis L","year":"2015","unstructured":"Ellis L, Loda M. Advanced neuroendocrine prostate tumors regress to stemness. Proc Natl Acad Sci U S A. 2015;112(47):14406\u20137.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"ref32","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1038\/s41419-020-03279-y","article-title":"JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma","volume":"11","author":"Macedo-Silva C","year":"2020","unstructured":"Macedo-Silva C, Miranda-Gon\u00e7alves V, Lameirinhas A, Lencart J, Pereira A, Lobo J, et al. JmjC-KDMs KDM3A and KDM6B modulate radioresistance under hypoxic conditions in esophageal squamous cell carcinoma. Cell Death Dis. 2020;11(12):1068.","journal-title":"Cell Death Dis"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/www.researchsquare.com\/article\/rs-5614729\/v1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.researchsquare.com\/article\/rs-5614729\/v1.html","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T07:11:42Z","timestamp":1751613102000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.researchsquare.com\/article\/rs-5614729\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,6]]},"references-count":32,"URL":"https:\/\/doi.org\/10.21203\/rs.3.rs-5614729\/v1","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1038\/s41420-025-02597-4","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,2,6]]},"subtype":"preprint"}}