{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:00:47Z","timestamp":1789675247920,"version":"4.0.1"},"reference-count":68,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T00:00:00Z","timestamp":1733356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nieders\u00e4chsische Krebsgesellschaft e.V."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, due in part to early invasion and metastasis, which in turn involves epithelial\u2013mesenchymal transition (EMT) of the cancer cells. Prompted by the discovery that two PDAC cell lines of the quasi-mesenchymal subtype (PANC-1, MIA PaCa-2) exhibit neuroendocrine differentiation (NED), we asked whether NED is associated with EMT. Using real-time PCR and immunoblotting, we initially verified endogenous expressions of various NED markers, i.e., chromogranin A (CHGA), synaptophysin (SYP), somatostatin receptor 2 (SSTR2), and SSTR5 in PANC-1 and MIA PaCa-2 cells. By means of immunohistochemistry, the expressions of CHGA, SYP, SSTR2, and the EMT markers cytokeratin 7 (CK7) and vimentin could be allocated to the neoplastic ductal epithelial cells of pancreatic ducts in surgically resected tissues from patients with PDAC. In HPDE6c7 normal pancreatic duct epithelial cells and in epithelial subtype BxPC-3 PDAC cells, the expression of CHGA, SYP, and neuron-specific enolase 2 (NSE) was either undetectable or much lower than in PANC-1 and MIA PaCa-2 cells. Parental cultures of PANC-1 cells exhibit EM plasticity (EMP) and harbor clonal subpopulations with both M- and E-phenotypes. Of note, M-type clones were found to display more pronounced NED than E-type clones. Inducing EMT in parental cultures of PANC-1 cells by treatment with transforming growth factor-\u03b21 (TGF-\u03b21) repressed epithelial genes and co-induced mesenchymal and NED genes, except for SSTR5. Surprisingly, treatment with bone morphogenetic protein (BMP)-7 differentially affected gene expressions in PANC-1, MIA PaCa-2, BxPC-3, and HPDE cells. It synergized with TGF-\u03b21 in the induction of vimentin, SNAIL, SSTR2, and NSE but antagonized it in the regulation of CHGA and SSTR5. Phospho-immunoblotting in M- and E-type PANC-1 clones revealed that both TGF-\u03b21 and, surprisingly, also BMP-7 activated SMAD2 and SMAD3 and that in M- but not E-type clones BMP-7 was able to dramatically enhance the activation of SMAD3. From these data, we conclude that in EMT of PDAC cells mesenchymal and NED markers are co-regulated, and that mesenchymal\u2013epithelial transition (MET) is associated with a loss of both the mesenchymal and NED phenotypes. Analyzing NED in another tumor type, small cell carcinoma of the ovary hypercalcemic type (SCCOHT), revealed that two model cell lines of this disease (SCCOHT-1, BIN-67) do express CDH1, SNAI1, VIM, CHGA, SYP, ENO2, and SSTR2, but that in contrast to BMP-7, none of these genes was transcriptionally regulated by TGF-\u03b21. Likewise, in BIN-67 cells, BMP-7 was able to reduce proliferation, while in SCCOHT-1 cells this occurred only upon combined treatment with TGF-\u03b2 and BMP-7. We conclude that in PDAC-derived tumor cells, NED is closely linked to EMT and TGF-\u03b2 signaling, which may have implications for the therapeutic use of TGF-\u03b2 inhibitors in PDAC management.<\/jats:p>","DOI":"10.3390\/cells13232010","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T09:30:18Z","timestamp":1733391018000},"page":"2010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Characterization of Epithelial\u2013Mesenchymal and Neuroendocrine Differentiation States in Pancreatic and Small Cell Ovarian Tumor Cells and Their Modulation by TGF-\u03b21 and BMP-7"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7552-2087","authenticated-orcid":false,"given":"Hendrik","family":"Ungefroren","sequence":"first","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein, Campus L\u00fcbeck, 23538 L\u00fcbeck, Germany"},{"name":"Institute of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"von der Ohe","sequence":"additional","affiliation":[{"name":"Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Surgery, University Hospital Schleswig-Holstein, Campus L\u00fcbeck, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yola","family":"G\u00e4tje","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein, Campus L\u00fcbeck, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olha","family":"Lapshyna","sequence":"additional","affiliation":[{"name":"Department of Surgery, University Hospital Schleswig-Holstein, Campus L\u00fcbeck, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Schrader","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Hamburg-Eppendorf, 20251 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Lehnert","sequence":"additional","affiliation":[{"name":"Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire (UHCW), Coventry CV2 2DX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8314-2682","authenticated-orcid":false,"given":"Jens-Uwe","family":"Marquardt","sequence":"additional","affiliation":[{"name":"First Department of Medicine, University Hospital Schleswig-Holstein, Campus L\u00fcbeck, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Konukiewitz","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2481-7547","authenticated-orcid":false,"given":"Ralf","family":"Hass","sequence":"additional","affiliation":[{"name":"Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s40164-020-00184-0","article-title":"Molecular drivers and cells of origin in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine carcinoma","volume":"9","author":"Gao","year":"2020","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"975","DOI":"10.5858\/arpa.2022-0417-RA","article-title":"Neoplastic Progression in Neuroendocrine Neoplasms of the Pancreas","volume":"148","author":"Luchini","year":"2023","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gradiz, R., Silva, H.C., Carvalho, L., Botelho, M.F., and Mota-Pinto, A. (2016). MIA PaCa-2 and PANC-1-pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci. Rep., 6.","DOI":"10.1038\/srep21648"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Schmidtlein, P.M., Volz, C., Braun, R., Th\u00fcrling, I., Lapshyna, O., Wellner, U.F., Konukiewitz, B., Lehnert, H., Marquardt, J.U., and Ungefroren, H. (2021). A Comparative Endocrine Trans-Differentiation Approach to Pancreatic Ductal Adenocarcinoma Cells with Different EMT Phenotypes Identifies Quasi-Mesenchymal Tumor Cells as Those with Highest Plasticity. Cancers, 13.","DOI":"10.3390\/cancers13184663"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Johnson, M.D., Stone, B., Thibodeau, B.J., Baschnagel, A.M., Galoforo, S., Fortier, L.E., Ketelsen, B., Ahmed, S., Kelley, Z., and Hana, A. (2017). The significance of Trk receptors in pancreatic cancer. Tumour Biol., 39.","DOI":"10.1177\/1010428317692256"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ungefroren, H., Th\u00fcrling, I., F\u00e4rber, B., Kowalke, T., Fischer, T., De Assis, L.V.M., Braun, R., Castven, D., Oster, H., and Konukiewitz, B. (2022). The Quasimesenchymal Pancreatic Ductal Epithelial Cell Line PANC-1-A Useful Model to Study Clonal Heterogeneity and EMT Subtype Shifting. Cancers, 14.","DOI":"10.3390\/cancers14092057"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/1097-0142(19820101)49:1<188::AID-CNCR2820490137>3.0.CO;2-D","article-title":"Small cell carcinoma of the ovary with hypercalcemia: A report of eleven cases","volume":"49","author":"Dickersin","year":"1982","journal-title":"Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1006\/gyno.1995.1092","article-title":"Small cell carcinoma of the hypercalcemic type in the ovary","volume":"57","author":"Young","year":"1995","journal-title":"Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"765","DOI":"10.3892\/ijo.2012.1468","article-title":"A tumor-derived population (SCCOHT-1) as cellular model for a small cell ovarian carcinoma of the hypercalcemic type","volume":"41","author":"Otte","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/jbmr.5650010309","article-title":"Differential cyclic AMP responses to calcitonen among human ovarian carcinoma cell lines: A calcitonin-responsive line derived from a rare tumor type","volume":"1","author":"Upchurch","year":"1986","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1750-1172-8-33","article-title":"Small cell ovarian carcinoma: Genomic stability and responsiveness to therapeutics","volume":"8","author":"Gamwell","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s13023-014-0126-4","article-title":"In vitro and in vivo therapeutic approach for a small cell carcinoma of the ovary hypercalcaemic type using a SCCOHT-1 cellular model","volume":"9","author":"Otte","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hass, R., von der Ohe, J., and Ungefroren, H. (2020). The intimate relationship among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to be exploited for therapeutic purposes. Cancers, 12.","DOI":"10.3390\/cancers12123674"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Nouri, M., Ratther, E., Stylianou, N., Nelson, C.C., Hollier, B.G., and Williams, E.D. (2014). Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: An opportunity for intervention. Front. Oncol., 4.","DOI":"10.3389\/fonc.2014.00370"},{"key":"ref_15","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","year":"2018","journal-title":"Biochim. Biophys. Acta Rev. Cancer."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.critrevonc.2014.05.008","article-title":"Neuroendocrine differentiation in prostate cancer: Current and emerging therapy strategies","volume":"92","author":"Conteduca","year":"2014","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hu, C.D., Choo, R., and Huang, J. (2015). Neuroendocrine differentiation in prostate cancer: A mechanism of radioresistance and treatment failure. Front. Oncol., 5.","DOI":"10.3389\/fonc.2015.00090"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1016\/j.jid.2021.01.012","article-title":"Classical and Variant Merkel Cell Carcinoma Cell Lines Display Different Degrees of Neuroendocrine Differentiation and Epithelial-Mesenchymal Transition","volume":"141","author":"Gravemeyer","year":"2021","journal-title":"J. Invest. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Groves, S.M., Panchy, N., Tyson, D.R., Harris, L.A., Quaranta, V., and Hong, T. (2023). Involvement of Epithelial-Mesenchymal Transition Genes in Small Cell Lung Cancer Phenotypic Plasticity. Cancers, 15.","DOI":"10.3390\/cancers15051477"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Luley, K.B., Biedermann, S.B., K\u00fcnstner, A., Busch, H., Franzenburg, S., Schrader, J., Grabowski, P., Wellner, U.F., Keck, T., and Brabant, G. (2020). A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1. Cancers, 12.","DOI":"10.3390\/cancers12030691"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1158\/1541-7786.MCR-07-2073","article-title":"The effect of transforming growth factor beta on human neuroendocrine tumor BON cell proliferation and differentiation is mediated through somatostatin signaling","volume":"6","author":"Leu","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Ungefroren, H., K\u00fcnstner, A., Busch, H., Franzenburg, S., Luley, K., Viol, F., Schrader, J., Konukiewitz, B., Wellner, U.F., and Meyh\u00f6fer, S.M. (2022). Differential Effects of Somatostatin, Octreotide, and Lanreotide on Neuroendocrine Differentiation and Proliferation in Established and Primary NET Cell Lines: Possible Crosstalk with TGF-\u03b2 Signaling. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415868"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ajur.2018.11.001","article-title":"Prostate tumor neuroendocrine differentiation via EMT: The road less traveled","volume":"6","author":"Dicken","year":"2019","journal-title":"Asian J. Urol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Li, R.X., Yiu, W.H., and Tang, S.C. (2015). Role of bone morphogenetic protein-7 in renal fibrosis. Front. Physiol., 6.","DOI":"10.3389\/fphys.2015.00114"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pan, Q., Wang, Y.Q., Li, G.M., Duan, X.Y., and Fan, J.G. (2015). Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells. Biomed. Res. Int., 2015.","DOI":"10.1155\/2015\/935903"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1111\/j.1349-7006.2009.01301.x","article-title":"Bone morphogenetic protein 7 induces mesenchymal-to-epithelial transition in melanoma cells, leading to inhibition of metastasis","volume":"100","author":"Na","year":"2009","journal-title":"Cancer Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8094","DOI":"10.1074\/jbc.M413102200","article-title":"Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney","volume":"280","author":"Zeisberg","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.3892\/etm.2012.720","article-title":"Bone morphogenetic protein-7 regulates Snail signaling in carbon tetrachloride-induced fibrosis in the rat liver","volume":"4","author":"Bi","year":"2012","journal-title":"Exp. Ther. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kim, S., Jeong, C.H., Song, S.H., Um, J.E., Kim, H.S., Yun, J.S., Han, D., Cho, E.S., Nam, B.Y., and Yook, J.I. (2020). Micellized Protein Transduction Domain-Bone Morphogenetic Protein-7 Efficiently Blocks Renal Fibrosis Via Inhibition of Transforming Growth Factor-Beta-Mediated Epithelial-Mesenchymal Transition. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.591275"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1039\/C5TX00471C","article-title":"Bone morphogenetic protein-7 prevented epithelial-mesenchymal transition in RLE-6TN cells","volume":"5","author":"Wang","year":"2016","journal-title":"Toxicol. Res."},{"key":"ref_31","first-page":"763","article-title":"A micellized bone morphogenetic protein-7 prodrug ameliorates liver fibrosis by suppressing transforming growth factor-\u03b2 signaling","volume":"12","author":"Cho","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1158\/1541-7786.MCR-17-0163","article-title":"Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model","volume":"16","author":"Benten","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31640","DOI":"10.18632\/oncotarget.5151","article-title":"c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations","volume":"6","author":"Otte","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","first-page":"e62541","article-title":"Organotypic Slice Cultures as Preclinical Models of Tumor Microenvironment in Primary Pancreatic Cancer and Metastasis","volume":"172","author":"Braun","year":"2021","journal-title":"J. Vis. Exp."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Witte, D., Otterbein, H., F\u00f6rster, M., Giehl, K., Zeiser, R., Lehnert, H., and Ungefroren, H. (2017). Negative regulation of TGF-\u03b21-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-15170-6"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ungefroren, H., Braun, R., Lapshyna, O., Konukiewitz, B., Wellner, U.F., Lehnert, H., and Marquardt, J.U. (2022). Suppressive Role of ACVR1\/ALK2 in Basal and TGF\u03b21-Induced Cell Migration in Pancreatic Ductal Adenocarcinoma Cells and Identification of a Self-Perpetuating Autoregulatory Loop Involving the Small GTPase RAC1b. Biomedicines, 10.","DOI":"10.3390\/biomedicines10102640"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1158\/1078-0432.CCR-06-2926","article-title":"Epithelial to mesenchymal transition: Expression of the regulators snail, slug, and twist in pancreatic cancer","volume":"13","author":"Hotz","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hosseinalizadeh, H., Hussain, Q.M., Poshtchaman, Z., Ahsan, M., Amin, A.H., Naghavi, S., and Mahabady, M.K. (2024). Emerging insights into keratin 7 roles in tumor progression and metastasis of cancers. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1243871"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zinn, R., Otterbein, H., Lehnert, H., and Ungefroren, H. (2019). RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition. Cells, 8.","DOI":"10.3390\/cells8121569"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1124\/mol.62.1.65","article-title":"SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7","volume":"62","author":"Inman","year":"2002","journal-title":"Mol. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/jcp.1041650118","article-title":"Increased tumorigenicity in the human pancreatic cell line MIA PaCa-2 is associated with an aberrant regulation of an IGF-1 autocrine loop and lack of expression of the TGF-beta type RII receptor","volume":"165","author":"Freeman","year":"1995","journal-title":"J. Cell Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/dbio.2001.0388","article-title":"Intracellular BMP signaling regulation in vertebrates: Pathway or network?","volume":"239","author":"Cho","year":"2001","journal-title":"Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13461","DOI":"10.1074\/jbc.M010981200","article-title":"Transcriptional activation of mouse sst2 somatostatin receptor promoter by transforming growth factor-beta. Involvement of Smad4","volume":"276","author":"Puente","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_44","first-page":"12461","article-title":"CD105 expression is associated with invasive capacity in ovarian cancer and promotes invasiveness by inhibiting NDRG1 and regulating the epithelial-mesenchymal transition","volume":"13","author":"Zhang","year":"2021","journal-title":"Am. J. Transl. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3659","DOI":"10.1091\/mbc.e16-06-0427","article-title":"Molecular signatures of mu opioid receptor and somatostatin receptor 2 in pancreatic cancer","volume":"27","author":"Jorand","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Gil, J., Marques-Pamies, M., Valassi, E., Serra, G., Salinas, I., Xifra, G., Casano-Sancho, P., Carrato, C., Biagetti, B., and Sesmilo, G. (2023). Molecular characterization of epithelial-mesenchymal transition and medical treatment related-genes in non-functioning pituitary neuroendocrine tumors. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1129213"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1093\/carcin\/bgn274","article-title":"Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2","volume":"30","author":"Gordon","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1007\/s12672-011-0084-4","article-title":"PI3K, Erk signaling in BMP7-induced epithelial-mesenchymal transition (EMT) of PC-3 prostate cancer cells in 2- and 3-dimensional cultures","volume":"2","author":"Lim","year":"2011","journal-title":"Horm. Cancer."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/s41374-021-00661-y","article-title":"Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1\/5 signaling pathway","volume":"101","author":"Gao","year":"2021","journal-title":"Lab. Investig."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1465-9921-14-36","article-title":"Bone morphogenetic proteins enhance an epithelial-mesenchymal transition in normal airway epithelial cells during restitution of a disrupted epithelium","volume":"14","author":"McCormack","year":"2013","journal-title":"Respir. Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Sruthi, K.K., Natani, S., and Ummanni, R. (2024). Tumor protein D52 (isoform 3) induces NF-\u03baB-STAT3 mediated EMT driving neuroendocrine differentiation of prostate cancer cells. Int. J. Biochem. Cell Biol., 166.","DOI":"10.1016\/j.biocel.2023.106493"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1002\/pros.24535","article-title":"MicroRNA-147b induces neuroendocrine differentiation of prostate cancer cells by targeting ribosomal protein RPS15A","volume":"83","author":"Natani","year":"2023","journal-title":"Prostate"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1186\/s12964-024-01886-2","article-title":"Human mesenchymal stroma\/stem-like cell-derived taxol-loaded EVs\/exosomes transfer anti-tumor microRNA signatures and express enhanced SDF-1-mediated tumor tropism","volume":"22","author":"Hass","year":"2024","journal-title":"Cell Commun. Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/pros.21132","article-title":"Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells","volume":"70","author":"McKeithen","year":"2010","journal-title":"Prostate"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Bery, F., Cancel, M., Gu\u00e9guinou, M., Potier-Cartereau, M., Vandier, C., Chant\u00f4me, A., Guibon, R., Bruy\u00e8re, F., Fromont, G., and Mah\u00e9o, K. (2021). Zeb1 and SK3 Channel Are Up-Regulated in Castration-Resistant Prostate Cancer and Promote Neuroendocrine Differentiation. Cancers, 13.","DOI":"10.3390\/cancers13122947"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eadc9142","DOI":"10.1126\/scisignal.adc9142","article-title":"MCTP1 increases the malignancy of androgen-deprived prostate cancer cells by inducing neuroendocrine differentiation and EMT","volume":"17","author":"Liu","year":"2024","journal-title":"Sci. Signal."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Natani, S., Dhople, V.M., Parveen, A., Sruthi, K.K., Khilar, P., Bhukya, S., and Ummanni, R. (2021). AMPK\/SIRT1 signaling through p38MAPK mediates Interleukin-6 induced neuroendocrine differentiation of LNCaP prostate cancer cells. Biochim. Biophys. Acta Mol. Cell Res., 1868.","DOI":"10.1016\/j.bbamcr.2021.119085"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.2174\/1871520616666160425105257","article-title":"Epigenetic and miRNAs Dysregulation in Prostate Cancer: The role of Nutraceuticals","volume":"16","author":"Bosutti","year":"2016","journal-title":"Anticancer. Agents Med. Chem."},{"key":"ref_59","first-page":"4222","article-title":"Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation","volume":"61","author":"Ellenrieder","year":"2001","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ungefroren, H., Konukiewitz, B., Braun, R., Wellner, U.F., Lehnert, H., and Marquardt, J.U. (2023). TAp73 Inhibits EMT and Cell Migration in Pancreatic Cancer Cells through Promoting SMAD4 Expression and SMAD4-Dependent Inhibition of ERK Activation. Cancers, 15.","DOI":"10.20944\/preprints202306.1910.v1"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1038\/cdd.2016.18","article-title":"TAp73 loss favors Smad-independent TGF-\u03b2 signaling that drives EMT in pancreatic ductal adenocarcinoma","volume":"23","author":"Thakur","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.canlet.2012.08.003","article-title":"Grape seed proanthocyanidins inhibit migration potential of pancreatic cancer cells by promoting mesenchymal-to-epithelial transition and targeting NF-\u03baB","volume":"334","author":"Prasad","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41467-018-06958-9","article-title":"CDK4\/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary","volume":"10","author":"Xue","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/cac2.12198","article-title":"Depression accelerates gastric cancer invasion and metastasis by inducing a neuroendocrine phenotype via the catecholamine\/beta(2)-AR\/MACC1 axis","volume":"41","author":"Pan","year":"2021","journal-title":"Cancer Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"19159","DOI":"10.18632\/oncotarget.24937","article-title":"MicroRNA-652 induces NED in LNCaP and EMT in PC3 prostate cancer cells","volume":"9","author":"Nam","year":"2018","journal-title":"Oncotarget"},{"key":"ref_66","first-page":"928","article-title":"Expression of receptor for advanced glycation end products (RAGE) and MMP-9 in human pancreatic cancer cells","volume":"51","author":"Takada","year":"2004","journal-title":"Hepatogastroenterology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1007\/s00018-015-2003-2","article-title":"Ionizing radiation induces a motile phenotype in human carcinoma cells in vitro through hyperactivation of the TGF-beta signaling pathway","volume":"73","author":"Carl","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"78","DOI":"10.18632\/oncotarget.1569","article-title":"Perspectives of TGF-beta inhibition in pancreatic and hepatocellular carcinomas","volume":"5","author":"Neuzillet","year":"2014","journal-title":"Oncotarget"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/23\/2010\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:47:53Z","timestamp":1760114873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/23\/2010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,5]]},"references-count":68,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["cells13232010"],"URL":"https:\/\/doi.org\/10.3390\/cells13232010","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,5]]}}}