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Adv."],"published-print":{"date-parts":[[2026,7,17]]},"abstract":"<jats:p>Neuroblastoma, a pediatric cancer derived from sympathetic ganglia of the peripheral nervous system, frequently metastasizes, driving poor outcomes. Primary neuroblastomas are well-characterized, but the mechanisms underlying metastasis remain poorly understood. Here, by using single-cell and spatial multiomics, we identified that lymph node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors. In addition, compared to primary adrenal masses, the metastatic niche display increased immunosuppressive myeloid programs, heightened immune checkpoint signaling, and lymphocyte exhaustion, which are indicative of immune evasion and dysfunction. Notably, metastatic neuroblastomas show elevated eIF4F translation machinery and XPO1 levels. Dual inhibition of eIF4A and XPO1 synergistically halted tumor growth and prolonged survival in xenograft models. Together, our multiomics studies reveal the molecular and cellular plasticity that contributes to therapy resistance and highlight exploitable therapeutic vulnerabilities in high-risk metastatic neuroblastomas.<\/jats:p>","DOI":"10.1126\/sciadv.aec6749","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:58:48Z","timestamp":1784311128000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell and spatial omics reveals region-specific plasticity and therapeutic vulnerabilities in metastatic high-risk neuroblastoma"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7285-3606","authenticated-orcid":true,"given":"Lai Man Natalie","family":"Wu","sequence":"first","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."},{"name":"Medpace Inc., Cincinnati, OH 45227, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6044-5624","authenticated-orcid":true,"given":"Janet L.","family":"Oblinger","sequence":"additional","affiliation":[{"name":"Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH 43215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dazhuan","family":"Xin","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohit","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3447-897X","authenticated-orcid":true,"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4501-4740","authenticated-orcid":true,"given":"Mike","family":"Adam","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Lopez-Nunez","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-7264","authenticated-orcid":true,"given":"Sara","family":"Szabo","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"von Allmen","sequence":"additional","affiliation":[{"name":"Division of Surgery, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long-Sheng","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children\u2019s Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH 43215, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5154-3134","authenticated-orcid":true,"given":"Brian D.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Riley Children\u2019s Health, Pediatric Cancer and Blood Disorders, Indiana University MSA Indianapolis, IN 46202, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-9014","authenticated-orcid":true,"given":"Qing Richard","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH 45229, USA."},{"name":"Department of Pediatrics, O\u2019Neal Comprehensive Cancer Center, Marnix E. 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