{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:23:25Z","timestamp":1787729005600,"version":"build-2784847793"},"reference-count":41,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Upper tract urothelial carcinoma (UTUC) is a rare, aggressive malignancy representing 5%\u201210% of urothelial carcinomas. Its basal subtype remains understudied but is preferentially associated with muscle invasion and poorer disease\u2010specific survival (DSS). Although the genomic landscape of UTUC has been extensively profiled, current bulk transcriptomic classification cannot resolve cellular heterogeneity or spatial organisation, potentially obscuring subtype\u2010specific microenvironmental programs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated single\u2010cell RNA sequencing and spatial transcriptomics to resolve relationships among molecular subtype, muscle invasion and cellular heterogeneity within the UTUC microenvironment. Cellular communication and multiscale spatial analyses identified spatial programs, with tissue\u2010level validation by multiplex immunofluorescence. These programs were further examined in external bladder cancer datasets spanning single\u2010cell, spatial and GeoMx platforms. SPP1 knockdown in J82 cells tested epithelial\u2010intrinsic effects. We evaluated the subtype\u2010discriminatory and prognostic relevance of SPP1 in the Japan\u2010UTUC cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Basal UTUC exhibited an immune\u2012stromal\u2010enriched microenvironment primarily associated with molecular subtype rather than pathological stage. Within basal tumours, muscle invasion coincided with increased heterogeneity and two spatial programs. A conserved SPP1\n                      <jats:sup>+<\/jats:sup>\n                      tumour\u2010associated macrophage\u2012FAP\n                      <jats:sup>+<\/jats:sup>\n                      myofibroblast boundary program was associated with myeloid immunosuppression and extracellular matrix remodelling. External datasets provided convergent support for its components and localisation near basal\u2010high epithelium at invasive margins. A more heterogeneous angiogenic program involved VEGFA\n                      <jats:sup>+<\/jats:sup>\n                      tumour\u2010associated neutrophil\u2012CXCR4\n                      <jats:sup>+<\/jats:sup>\n                      tip endothelial interactions. At the epithelial level, SPP1 knockdown reduced J82 cell viability, migration and invasion. SPP1 discriminated basal from luminal tumours (area under the receiver operating characteristic curve (AUC)\u00a0=\u00a0.839), and higher expression remained associated with poorer DSS after pathological stage adjustment (hazard ratio\u00a0=\u00a01.17, 95% confidence interval\u00a0=\u00a01.01\u20121.35,\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a0.036).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Basal UTUC has a largely stage\u2010independent, immune\u2012stromal\u2010enriched background that is spatially reorganised with muscle invasion, with an SPP1\u2010associated myeloid\u2012stromal boundary program as its most reproducible feature. Spatial, functional and clinical evidence supports the prognostic value of SPP1 and warrants its evaluation as a therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70782","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T07:11:31Z","timestamp":1787555491000},"source":"Crossref","is-referenced-by-count":0,"title":["SPP1\u2010driven spatial niche remodelling defines aggressive progression in the basal subtype of upper tract urothelial carcinoma"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4124-7113","authenticated-orcid":false,"given":"Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Urology The First Affiliated Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Guangdong Provincial Key Laboratory of Urological Diseases Guangzhou Medical University  Guangzhou China"},{"name":"Nanshan School Guangzhou Medical University  Guangzhou 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