{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T16:32:38Z","timestamp":1780677158634,"version":"3.54.1"},"reference-count":98,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RC2025"],"award-info":[{"award-number":["RC2025"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cutaneous melanoma is a highly aggressive skin cancer prone to relapse and metastasis. Surgery is often curative when combined with early screening and prevention. However, in recurrent or advanced disease, the development of new targeted and immune therapies has demonstrated promising clinical outcomes, although the acquisition of resistance limits their effectiveness. Thus, new therapeutic approaches are needed. Emerging data indicate that the Hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly reactivated in melanoma and may represent a promising therapeutic target. Here, we demonstrate its chronic up-modulation in a panel of patient-derived cell lines and, by investigating the underlying molecular mechanisms, we excluded mutations in the principal components of the pathway. We observed reduced PTCH1 and SUFU repressors expression and GLI2 upregulation as common melanoma features. At the same time, copious SHH release, the principal PTCH1 ligand, evidenced autocrine Hh signaling activation. Consistently, a tendency of greater level of this factor resulted higher in the blood of patients compared to controls, confirming the relevance of ligand-dependent trigger in melanoma. The therapeutic potential of inhibiting the Hh pathway is highlighted by the reduced proliferation and migration observed in the presence of clinically approved pharmacological Hh antagonists. Profiling inflammatory mediators revealed significant modulation upon treatment with SMO inhibitors, possibly affecting chemotactic and immune functions. Collectively, these findings provide deeper insight into the role of the Hh pathway in melanoma and support the potential repurposing of Hh inhibitors as therapeutic agents for melanoma.<\/jats:p>","DOI":"10.3390\/ijms27020762","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T14:57:25Z","timestamp":1768229845000},"page":"762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aberrant Activation of the Hedgehog Pathway in Cutaneous Melanoma: Therapeutic Potential of Pharmacological Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"given":"Federica","family":"Papaccio","sequence":"first","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6640-7418","authenticated-orcid":false,"given":"Ramona","family":"Marrapodi","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Caputo","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5316-8937","authenticated-orcid":false,"given":"Emilia","family":"Migliano","sequence":"additional","affiliation":[{"name":"Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4908-5271","authenticated-orcid":false,"given":"Elisa","family":"Melucci","sequence":"additional","affiliation":[{"name":"Department of Pathology, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-5917","authenticated-orcid":false,"given":"Stefano","family":"Scalera","sequence":"additional","affiliation":[{"name":"Biostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Cota","sequence":"additional","affiliation":[{"name":"Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Maugeri-Sacc\u00e0","sequence":"additional","affiliation":[{"name":"Biostatistics, Bioinformatics and Clinical Trial Center, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-5500","authenticated-orcid":false,"given":"Barbara","family":"Bellei","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5996","DOI":"10.1038\/s41598-025-90485-3","article-title":"Global, Regional, and National Trends in the Burden of Melanoma and Non-Melanoma Skin Cancer: Insights from the Global Burden of Disease Study 1990\u20132021","volume":"15","author":"Zhou","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Conforti, C., and Zalaudek, I. (2021). Epidemiology and Risk Factors of Melanoma: A Review. Dermatol. Pract. Concept., 11.","DOI":"10.5826\/dpc.11S1a161S"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Manganelli, M., Stabile, G., Scharf, C., Brunetti, A.P., Paolino, G., Giuffrida, R., Bigotto, G.D., Damiano, G., Mercuri, S.R., and Sallustio, F. (2025). Skin Photodamage and Melanomagenesis: A Comprehensive Review. Cancers, 17.","DOI":"10.3390\/cancers17111784"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Garrison, Z.R., Hall, C.M., Fey, R.M., Clister, T., Khan, N., Nichols, R., and Kulkarni, R.P. (2023). Advances in Early Detection of Melanoma and the Future of at-Home Testing. Life, 13.","DOI":"10.3390\/life13040974"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"797","DOI":"10.3892\/etm.2021.10229","article-title":"Updates and New Medical Treatments for Vitiligo (Review)","volume":"22","author":"Wollina","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104276","DOI":"10.1016\/j.critrevonc.2024.104276","article-title":"The Treatment of Advanced Melanoma: Current Approaches and New Challenges","volume":"196","author":"Boutros","year":"2024","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.phrs.2019.01.014","article-title":"Targeting Hedgehog Signaling Pathway: Paving the Road for Cancer Therapy","volume":"141","author":"Salaritabar","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yu, M., Qin, K., Fan, J., Zhao, G., Zhao, P., Zeng, W., Chen, C., Wang, A., Wang, Y., and Zhong, J. (2023). The Evolving Roles of Wnt Signaling in Stem Cell Proliferation and Differentiation, the Development of Human Diseases, and Therapeutic Opportunities. Genes Dis., 11.","DOI":"10.1016\/j.gendis.2023.04.042"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Abe, Y., and Tanaka, N. (2017). Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer. J. Dev. Biol., 5.","DOI":"10.3390\/jdb5040012"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1016\/j.jid.2021.11.026","article-title":"Hedgehog Signaling in Papillary Fibroblasts is Essential for Hair Follicle Regeneration during Wound Healing","volume":"142","author":"Frech","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wang, W., Li, F., Wang, J., Liu, Z., Tian, M., Wang, Z., Li, H., Qu, J., Chen, Y., and Hou, L. (2023). Disrupting Hedgehog Signaling in Melanocytes by SUFU Knockout Leads to Ocular Melanocytosis and Anterior Segment Malformation. Dis. Model. Mech., 16.","DOI":"10.1242\/dmm.050210"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.jid.2017.10.032","article-title":"Keratinocyte Sonic Hedgehog Upregulation Drives the Development of Giant Congenital Nevi Via Paracrine Endothelin-1 Secretion","volume":"138","author":"Chitsazan","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.stem.2015.02.006","article-title":"Basal Cell Carcinoma Preferentially Arises from Stem Cells within Hair Follicle and Mechanosensory Niches","volume":"16","author":"Peterson","year":"2015","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1093\/emboj\/cdg271","article-title":"The Magnitude of Hedgehog Signaling Activity Defines Skin Tumor Phenotype","volume":"22","author":"Grachtchouk","year":"2003","journal-title":"EMBO J."},{"key":"ref_15","first-page":"5308","article-title":"Dissecting the Oncogenic Potential of Gli2: Deletion of an NH(2)-Terminal Fragment Alters Skin Tumor Phenotype","volume":"62","author":"Sheng","year":"2002","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00105-024-05352-5","article-title":"Alopecia due to Chemotherapeutics, Hedgehog Inhibitors, Targeted Antibody Therapies and Immune Checkpoint Inhibitors: Pathogenesis, Clinical Picture, Diagnostics and Prophylaxis","volume":"75","author":"Sachse","year":"2024","journal-title":"Dermatologie"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Choi, H., Shin, J.H., Kim, E.S., Park, S.J., Bae, I., Jo, Y.K., Jeong, I.Y., Kim, H., Lee, Y., and Park, H.C. (2016). Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168025"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1111\/j.1755-148X.2011.00893.x","article-title":"GLI2 and M-MITF transcription factors control exclusive gene expression programs and inversely regulate invasion in human melanoma cells","volume":"24","author":"Javelaud","year":"2011","journal-title":"Pig. Cell Mel. Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kim, N., and Lee, A. (2023). Oxidative Stress Induces Skin Pigmentation in Melasma by Inhibiting Hedgehog Signaling. Antioxidants, 12.","DOI":"10.3390\/antiox12111969"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41392-023-01559-5","article-title":"Hedgehog Signaling in Tissue Homeostasis, Cancers, and Targeted Therapies","volume":"8","author":"Jing","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e62","DOI":"10.1158\/1078-0432.CCR-17-0595","article-title":"Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome","volume":"23","author":"Foulkes","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Di Nardo, L., Pellegrini, C., Di Stefani, A., Ricci, F., Fossati, B., Del Regno, L., Carbone, C., Piro, G., Corbo, V., and Delfino, P. (2021). Molecular Alterations in Basal Cell Carcinoma Subtypes. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-92592-3"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1111\/cup.12819","article-title":"Pigmented Basal Cell Carcinoma: Increased Melanin or Increased Melanocytes?","volume":"43","author":"Brankov","year":"2016","journal-title":"J. Cutan. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00262-021-02966-9","article-title":"PTCH1 Mutation Promotes Antitumor Immunity and the Response to Immune Checkpoint Inhibitors in Colorectal Cancer Patients","volume":"71","author":"Wang","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16359","DOI":"10.1038\/s41598-019-52617-4","article-title":"Mutation of the PTCH1 Gene Predicts Recurrence of Breast Cancer","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ijc.28424","article-title":"Nonclassical Hedgehog-GLI Signaling and its Clinical Implications","volume":"135","author":"Shevde","year":"2014","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e377","DOI":"10.1002\/wdev.377","article-title":"Signaling in the Primary Cilium through the Lens of the Hedgehog Pathway","volume":"9","author":"Gigante","year":"2020","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s00018-015-2127-4","article-title":"Hedgehog Signaling Pathway: A Novel Model and Molecular Mechanisms of Signal Transduction","volume":"73","author":"Gorojankina","year":"2016","journal-title":"Cell Mol. Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.semcdb.2014.05.010","article-title":"Transcriptional Regulation of Graded Hedgehog Signaling","volume":"33","author":"Falkenstein","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3390\/ph6111429","article-title":"Hedgehog Pathway Blockade Inhibits Melanoma Cell Growth in Vitro and in Vivo","volume":"6","author":"Segura","year":"2013","journal-title":"Pharmaceuticals"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Giuntini, G., Monaci, S., Cau, Y., Mori, M., Naldini, A., and Carraro, F. (2020). Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII. Cancers, 12.","DOI":"10.3390\/cancers12103018"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Falsini, A., Giuntini, G., Mori, M., Ghirga, F., Quaglio, D., Cucinotta, A., Coppola, F., Filippi, I., Naldini, A., and Botta, B. (2024). Hedgehog Pathway Inhibition by Novel Small Molecules Impairs Melanoma Cell Migration and Invasion Under Hypoxia. Pharmaceuticals, 17.","DOI":"10.3390\/ph17020227"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5895","DOI":"10.1073\/pnas.0700776104","article-title":"Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK\/AKT pathways","volume":"104","author":"Stecca","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1007\/s13402-025-01050-z","article-title":"The MEK5\/ERK5 pathway promotes the activation of the Hedgehog\/GLI signaling in melanoma cells","volume":"48","author":"Tusa","year":"2025","journal-title":"Cell. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"43295","DOI":"10.18632\/oncotarget.9232","article-title":"The Role of Wnt\/\u0392-Catenin Signaling Pathway in Melanoma Epithelial-to-Mesenchymal-Like Switching: Evidences from Patients-Derived Cell Lines","volume":"7","author":"Kovacs","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/his.14814","article-title":"PRAME is a Useful Marker for the Differential Diagnosis of Melanocytic Tumours and Histological Mimics","volume":"82","author":"Chen","year":"2023","journal-title":"Histopathology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1007\/s10517-018-4051-8","article-title":"Role of IGFBP6 Protein in the Regulation of Epithelial-Mesenchymal Transition Genes","volume":"164","author":"Nikulin","year":"2018","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1016\/j.ajpath.2019.08.002","article-title":"The Role of MET in Melanoma and Melanocytic Lesions","volume":"189","author":"Zhou","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gao, Q., Li, N., Pan, Y., Chu, P., Zhou, Y., Jia, H., Cheng, Y., Xue, G., Song, J., and Zhang, Y. (2024). Hepatocyte Growth Factor Promotes Melanoma Metastasis through Ubiquitin-Specific Peptidase 22-Mediated Integrins Upregulation. Cancer Lett., 604.","DOI":"10.1016\/j.canlet.2024.217196"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3803","DOI":"10.1038\/onc.2013.358","article-title":"BMP4\/Thrombospondin-1 Loop Paracrinically Inhibits Tumor Angiogenesis and Suppresses the Growth of Solid Tumors","volume":"33","author":"Tsuchida","year":"2014","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s40170-025-00378-2","article-title":"Carboxylesterase 1-Mediated Endocannabinoid Metabolism in Skin: Role in Melanoma Progression in BRaf(V600E)\/Pten(-\/-) Mice","volume":"13","author":"Morozova","year":"2025","journal-title":"Cancer Metab."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Wang, C., Wang, Z., Yao, T., Zhou, J., and Wang, Z. (2022). The Immune-Related Role of Beta-2-Microglobulin in Melanoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.944722"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1186\/s12964-024-01812-6","article-title":"Interactions between Hedgehog Signaling Pathway and the Complex Tumor Microenvironment in Breast Cancer: Current Knowledge and Therapeutic Promises","volume":"22","author":"Liu","year":"2024","journal-title":"Cell. Commun. Signal."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1126\/science.272.5268.1668","article-title":"Human Homolog of Patched, a Candidate Gene for the Basal Cell Nevus Syndrome","volume":"272","author":"Johnson","year":"1996","journal-title":"Science"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.277.5329.1109","article-title":"Altered Neural Cell Fates and Medulloblastoma in Mouse Patched Mutants","volume":"277","author":"Goodrich","year":"1997","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nm0598-619","article-title":"Rhabdomyosarcomas and Radiation Hypersensitivity in a Mouse Model of Gorlin Syndrome","volume":"4","author":"Hahn","year":"1998","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wen, J., and Hadden, M.K. (2021). Medulloblastoma Drugs in Development: Current Leads, Trials and Drawbacks. Eur. J. Med. Chem., 215.","DOI":"10.1016\/j.ejmech.2021.113268"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Papaccio, F., Marrapodi, R., Eibenschutz, L., D\u2019Arino, A., Caputo, S., Marini, A., Scano, S., Presaghi, A., Cota, C., and Melucci, E. (2026). Resistance to SMO Inhibitors in Advanced Basal Cell Carcinoma: A Case Highlighting the Role of Molecular Tumor Profiling. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27010068"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Eibenschutz, L., Caputo, S., Camera, E., Carbone, A., Silipo, V., Migliano, E., Aurizi, C., Cota, C., Frascione, P., and Bellei, B. (2021). Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?. Cancers, 13.","DOI":"10.3390\/cancers13225858"},{"key":"ref_50","first-page":"1","article-title":"Mechanism and therapeutic potential of the hedgehog signaling pathway in cancer","volume":"40","author":"Cong","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"544","DOI":"10.4161\/cbt.28157","article-title":"Effects of Inhibition of Hedgehog Signaling on Cell Growth and Migration of Uveal Melanoma Cells","volume":"15","author":"Duan","year":"2014","journal-title":"Cancer Biol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"D\u2019Arcy, C., and Kiel, C. (2021). Cell Adhesion Molecules in Normal Skin and Melanoma. Biomolecules, 11.","DOI":"10.3390\/biom11081213"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Marrapodi, R., and Bellei, B. (2024). The Keratinocyte in the Picture Cutaneous Melanoma Microenvironment. Cancers, 16.","DOI":"10.3390\/cancers16050913"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Petitprez, F., Meylan, M., de Reyni\u00e8s, A., Saut\u00e8s-Fridman, C., and Fridman, W.H. (2020). The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00784"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Hanssen, F., Garcia, M.U., Folkersen, L., Pedersen, A.S., Lescai, F., Jodoin, S., Miller, E., Seybold, M., Wacker, O., and Smith, N. (2024). Scalable and Efficient DNA Sequencing Analysis on Different Compute Infrastructures Aiding Variant Discovery. NAR Genom. Bioinform., 6.","DOI":"10.1093\/nargab\/lqae031"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Newnes, H.V., Armitage, J.D., Buzzai, A.C., de Jong, E., Audsley, K.M., Barnes, S.A., Srinivasan, S., Serralha, M., Fear, V.S., and Guo, B.B. (2025). Interleukin-4 Modulates Type I Interferon to Augment Antitumor Immunity. Sci. Adv., 11.","DOI":"10.1126\/sciadv.adt3618"},{"key":"ref_57","first-page":"104","article-title":"Interleukin-4-Induced Natural Killer Cell Antitumor Activity in Metastatic Melanoma Patients","volume":"32","author":"Larsen","year":"2020","journal-title":"Eur. Cytokine Netw."},{"key":"ref_58","first-page":"2002","article-title":"Modulation of Human Melanoma Cells by Interleukin-4 and in Combination with Gamma-Interferon or Alpha-Tumor Necrosis Factor","volume":"51","author":"Hoon","year":"1991","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"McWilliams, E.M., Mele, J.M., Cheney, C., Timmerman, E.A., Fiazuddin, F., Strattan, E.J., Mo, X., Byrd, J.C., Muthusamy, N., and Awan, F.T. (2016). Therapeutic CD94\/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia. Oncoimmunology, 5.","DOI":"10.1080\/2162402X.2016.1226720"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"8687","DOI":"10.1158\/0008-5472.CAN-08-0449","article-title":"Endogenous interleukin-4 promotes tumor development by increasing tumor cell resistance to apoptosis","volume":"68","author":"Li","year":"2008","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Skeate, J.G., Otsmaa, M.E., Prins, R., Fernandez, D.J., Da Silva, D.M., and Kast, W.M. (2020). TNFSF14: LIGHTing the Way for Effective Cancer Immunotherapy. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00922"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3428","DOI":"10.1158\/0008-5472.CAN-04-3239","article-title":"Constitutive Expression and Costimulatory Function of LIGHT\/TNFSF14 on Human Melanoma Cells and Melanoma-Derived Microvesicles","volume":"65","author":"Mortarini","year":"2005","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"289","DOI":"10.2215\/CJN.0000000000000409","article-title":"Kidney After Liver Transplantation for all: Are You Kidneying Me?","volume":"19","author":"Kumar","year":"2024","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41374-019-0345-3","article-title":"CCL8 Secreted by Tumor-Associated Macrophages Promotes Invasion and Stemness of Glioblastoma Cells Via ERK1\/2 Signaling","volume":"100","author":"Zhang","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Reschke, R., Enk, A.H., and Hassel, J.C. (2024). Chemokines and Cytokines in Immunotherapy of Melanoma and Other Tumors: From Biomarkers to Therapeutic Targets. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25126532"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Motlak, M., Mathews, M., Al-Odat, O.S., and Pandey, M.K. (2024). Is it Possible to Treat Melanoma by Intercepting the CXCR4\/CXCL12 Pathway?. Cytokine, 179.","DOI":"10.1016\/j.cyto.2024.156629"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1080\/1744666X.2017.1384313","article-title":"Chemokines as Adjuvants for Immunotherapy: Implications for Immune Activation with CCL3","volume":"13","author":"Schaller","year":"2017","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.ajpath.2011.09.005","article-title":"Host-Derived MCP-1 and MIP-1\u03b1 Regulate Protective Anti-Tumor Immunity to Localized and Metastatic B16 Melanoma","volume":"180","author":"Nakasone","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Liu, N., Yan, M., Lu, C., Tao, Q., Wu, J., Zhou, Z., Chen, J., Chen, X., and Peng, C. (2025). Eravacycline Improves the Efficacy of Anti-PD1 Immunotherapy Via AP1\/CCL5 Mediated M1 Macrophage Polarization in Melanoma. Biomaterials, 314.","DOI":"10.1016\/j.biomaterials.2024.122815"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1046\/j.1523-1747.2002.01725.x","article-title":"The Role of Chemokines in Melanoma Tumor Growth and Metastasis","volume":"118","author":"Payne","year":"2002","journal-title":"J. Investig. Dermatol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/jid.2008.270","article-title":"Macrophage Inhibitory Cytokine-1 is Overexpressed in Malignant Melanoma and is Associated with Tumorigenicity","volume":"129","author":"Boyle","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4253","DOI":"10.1038\/s41467-023-39817-3","article-title":"Tumor-Derived GDF-15 Blocks LFA-1 Dependent T Cell Recruitment and Suppresses Responses to Anti-PD-1 Treatment","volume":"14","author":"Haake","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/CMR.0000000000000790","article-title":"Macrophage Inhibitory Cytokine-1 Produced by Melanoma Cells Contributes to Melanoma Tumor Growth and Metastasis in Vivo by Enhancing Tumor Vascularization","volume":"32","author":"Lee","year":"2022","journal-title":"Melanoma Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Wedel, S., Martic, I., Guerrero Navarro, L., Ploner, C., Pierer, G., Jansen-D\u00fcrr, P., and Cavinato, M. (2023). Depletion of Growth Differentiation Factor 15 (GDF15) Leads to Mitochondrial Dysfunction and Premature Senescence in Human Dermal Fibroblasts. Aging Cell, 22.","DOI":"10.1111\/acel.13752"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Li, H., Chen, B., Chen, Z., Luo, J., and Yang, B. (2025). Overexpression of Growth Differentiation Factor 15 Reduces Neuronal Cell Damage Induced by Oxygen-Glucose Deprivation\/Reoxygenation Via Inhibiting Endoplasmic Reticulum Stress-Mediated Ferroptosis. Dev. Neurobiol., 85.","DOI":"10.1002\/dneu.22957"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"E552","DOI":"10.1152\/ajpendo.00257.2024","article-title":"Secreted GDF15 Maintains Transcriptional Responses during DNA Damage-Mediated Senescence in Human Beta Cells","volume":"327","author":"Pipella","year":"2024","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/pcmr.12091","article-title":"Differential Expression and Tumor Necrosis Factor-Mediated Regulation of TNFRSF11b\/Osteoprotegerin Production by Human Melanomas","volume":"26","author":"Oliver","year":"2013","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.21873\/anticanres.12806","article-title":"OPG, OPN, EGF and VEGF Levels at Individual Breslow Score Stages in Malignant Melanoma","volume":"38","author":"Treskova","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.abd.2023.07.012","article-title":"Insulin Inhibits Melanoma Tumor Growth through the Expression of Activating Transcription Factor 4, without Detectable Expression of Transcription Factor CHOP: An in Vivo Model","volume":"99","author":"Padilha","year":"2024","journal-title":"An. Bras. Dermatol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Jalili, A., Mertz, K.D., Romanov, J., Wagner, C., Kalthoff, F., Stuetz, A., Pathria, G., Gschaider, M., Stingl, G., and Wagner, S.N. (2013). NVP-LDE225, a Potent and Selective SMOOTHENED Antagonist Reduces Melanoma Growth in Vitro and in Vivo. PLoS ONE, 8, Erratum in PLoS ONE 2013, 8.","DOI":"10.1371\/annotation\/ddd22094-5d8d-43ef-ad81-b95afe392ec7"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Kurtovi\u0107, M., Pite\u0161a, N., \u010conka\u0161, J., Hajpek, H., Vu\u010di\u0107, M., Musani, V., Ozreti\u0107, P., and Sabol, M. (2024). GLI Transcriptional Targets S100A7 and KRT16 show Upregulated Expression Patterns in Epidermis Overlying the Tumor Mass in Melanoma Samples. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116084"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Boateng, S.T., Roy, T., Agbo, M.E., Mahmud, M.A., Banang-Mbeumi, S., Chamcheu, R.N., Yadav, R.K., Bramwell, M., Pham, L.K., and Dang, D.D. (2024). Multifaceted Approach Toward Mapping Out the Anticancer Properties of Small Molecules Via in Vitro Evaluation on Melanoma and Nonmelanoma Skin Cancer Cells, and in Silico Target Fishing. Chem. Biol. Drug Des., 103.","DOI":"10.1111\/cbdd.14418"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Yue, S., Tang, L., Tang, Y., Tang, Y., Shen, Q., Ding, J., Chen, Y., Zhang, Z., Yu, T., and Zhang, Y.E. (2014). Requirement of Smurf-Mediated Endocytosis of Patched1 in Sonic Hedgehog Signal Reception. Elife, 3.","DOI":"10.7554\/eLife.02555"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1158\/1535-7163.MCT-13-0420","article-title":"Novel Neutralizing Hedgehog Antibody MEDI-5304 Exhibits Antitumor Activity by Inhibiting Paracrine Hedgehog Signaling","volume":"13","author":"Michaud","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nature01972","article-title":"Widespread Requirement for Hedgehog Ligand Stimulation in Growth of Digestive Tract Tumours","volume":"425","author":"Berman","year":"2003","journal-title":"Nature"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12943-016-0509-3","article-title":"Hedgehog Signaling: Modulation of Cancer Properies and Tumor Mircroenvironment","volume":"15","author":"Hanna","year":"2016","journal-title":"Mol. Cancer"},{"key":"ref_87","first-page":"5368","article-title":"Hedgehog Signaling in the Tumor Microenvironment","volume":"67","author":"Cuneo","year":"2007","journal-title":"Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1186\/s13046-024-03138-0","article-title":"Tumor-Derived GLI1 Promotes Remodeling of the Immune Tumor Microenvironment in Melanoma","volume":"43","author":"Giammona","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Shamsoon, K., Hiraki, D., Yoshida, K., Takabatake, K., Takebe, H., Yokozeki, K., Horie, N., Fujita, N., Nasrun, N.E., and Okui, T. (2023). The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment. Int. J. Mol. Sci., 24.","DOI":"10.21203\/rs.3.rs-2558728\/v1"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Wang, J., Cui, B., Li, X., Zhao, X., Huang, T., and Ding, X. (2023). The Emerging Roles of Hedgehog Signaling in Tumor Immune Microenvironment. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1171418"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1038\/sj.jid.5700827","article-title":"Targeting Tumor-Associated Macrophages and Inhibition of MCP-1 Reduce Angiogenesis and Tumor Growth in a Human Melanoma Xenograft","volume":"127","author":"Gazzaniga","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1007\/BF01526794","article-title":"Interleukin-4 Plus Tumor Necrosis Factor Alpha Augments the Antigenicity of Melanoma Cells","volume":"37","author":"Hoon","year":"1993","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1111\/cas.13294","article-title":"Critical Role of Glioma-Associated Oncogene Homolog 1 in Maintaining Invasive and Mesenchymal-Like Properties of Melanoma Cells","volume":"108","author":"Gunarta","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_94","first-page":"271","article-title":"Hedgehog Signaling, Epithelial-to-Mesenchymal Transition and miRNA (Review)","volume":"22","author":"Katoh","year":"2008","journal-title":"Int. J. Mol. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/hep.26147","article-title":"Inhibition of Hedgehog Signaling Attenuates Carcinogenesis in Vitro and Increases Necrosis of Cholangiocellular Carcinoma","volume":"57","author":"Kalnytska","year":"2013","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1093\/jnci\/djq257","article-title":"GLI2-Mediated Melanoma Invasion and Metastasis","volume":"102","author":"Alexaki","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.ccell.2015.02.002","article-title":"Smoothened Variants Explain the Majority of Drug Resistance in Basal Cell Carcinoma","volume":"27","author":"Atwood","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.molonc.2014.09.003","article-title":"Smoothened (SMO) Receptor Mutations Dictate Resistance to Vismodegib in Basal Cell Carcinoma","volume":"9","author":"Pricl","year":"2015","journal-title":"Mol. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/762\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T08:49:46Z","timestamp":1768985386000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/2\/762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,12]]},"references-count":98,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27020762"],"URL":"https:\/\/doi.org\/10.3390\/ijms27020762","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,12]]}}}