{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T05:46:13Z","timestamp":1791783973394,"version":"4.3.4"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T00:00:00Z","timestamp":1791676800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007533","name":"Kobayashi Foundation for Cancer Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007533","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015642","name":"Japan Lung Cancer Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015642","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP256f0137011"],"award-info":[{"award-number":["JP256f0137011"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K07649"],"award-info":[{"award-number":["23K07649"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Small\u2010cell lung carcinoma (SCLC) is a highly aggressive tumor with a dismal prognosis among lung cancers. Treatment is failing because of primary or rapidly developing secondary resistance. Recent molecular studies have suggested four SCLC subtypes with unique therapeutic vulnerabilities\u2014ASCL1, NEUROD1, POU2F3, and YAP. These subtypes still distinguish themselves by considerable intra\u2010tumoral heterogeneity and the influence of the microenvironmental context, which are both considered to be responsible for treatment resistance. We integrated in\u00a0situ hybridization\u2010based spatial transcriptomics with histological and protein\u2010expression analyses of 18 specimens, comprising 16 SCLCs, one atypical carcinoid, and one normal lung specimen. Systematic case\u2010by\u2010case analysis revealed multiple coexisting tumor states, including neuroendocrine and non\u2010neuroendocrine components, regional hypoxic states, and case\u2010specific\n                    <jats:italic>FABP7<\/jats:italic>\n                    \u2010positive and loss\u2010of\u2010chromosome\u2010Y\u2010associated populations. Integrative transcriptome clustering, copy number estimation, and exploratory trajectory analysis revealed transcriptional relationships among spatially coexisting tumor states, including phenotypically distinct tumor components with molecular features consistent with close clonal relationships in selected heterogeneous tumors. Furthermore, we identified immune signatures and uncovered a previously unrecognized\n                    <jats:italic>MMP12<\/jats:italic>\n                    \u2010positive tumor\u2010associated macrophage population, enriched at the tumor interface and spatially associated with necrotic and hypoxic regions. In\u00a0vitro co\u2010culture experiments further showed that direct contact with SCLC cells increased\n                    <jats:italic>MMP12<\/jats:italic>\n                    expression in macrophages, with hypoxia further enhancing its expression under specific conditions. Together, our study delineates the complex spatial architecture of SCLC by defining specific cellular programs and adjacent immune phenotypes that provide an organizational framework for understanding its marked intratumoral heterogeneity.\n                  <\/jats:p>","DOI":"10.1111\/cas.70555","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T05:26:57Z","timestamp":1791782817000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Atlas of Small Cell Lung Carcinoma Reveals Intratumoral Tumor\u2010State Heterogeneity and an\n                    <i>MMP12<\/i>\n                    <sup>+<\/sup>\n                    Macrophage Niche"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-0700-058X","authenticated-orcid":false,"given":"Naozane","family":"Nomura","sequence":"first","affiliation":[{"name":"Division of Molecular and Genomic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0423-3568","authenticated-orcid":false,"given":"Naoe","family":"Jimbo","sequence":"additional","affiliation":[{"name":"Division of Molecular and Genomic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Nakanishi","sequence":"additional","affiliation":[{"name":"Division of Molecular and Genomic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Division of Diagnostic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinobu","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences Kanazawa University  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences Kanazawa University  Kanazawa Japan"},{"name":"Department of Diagnostic Pathology Nara Medical University  Kashihara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daichi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Division of Molecular and Genomic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe Japan"},{"name":"Department of Molecular and Cellular Pathology, Graduate School of Medical Sciences Kanazawa University  Kanazawa Japan"},{"name":"The Garvan Institute of Medical Research  Darlinghurst New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroko","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology Kanazawa University Hospital  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsukasa","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Kanazawa University Hospital  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Koba","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Kanazawa University Hospital  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6151-2988","authenticated-orcid":false,"given":"Seiji","family":"Yano","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine Kanazawa University Hospital  Kanazawa Japan"},{"name":"WPI Nano Life Science Institute Kanazawa University  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isao","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery Kanazawa University  Kanazawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Micke","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Kodama","sequence":"additional","affiliation":[{"name":"Division of Molecular and Genomic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Shigeoka","sequence":"additional","affiliation":[{"name":"Division of Molecular and Genomic Pathology, Department of Pathology Kobe University Graduate School of Medicine  Kobe 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