{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:53:41Z","timestamp":1790927621707,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>KRAS G12C is the most common KRAS alteration in lung adenocarcinoma and has emerging therapeutic relevance. However, the spatial programs within primary tumors that accompany metastasis remain poorly understood. We profiled primary tumor tissues from four patients with KRAS G12C\u2010mutant lung adenocarcinoma, including two without metastasis and two with metastasis, using 10\u00d7 Visium spatial transcriptomics. Spatial clustering, differential expression, functional enrichment, and Robust Cell Type Decomposition (RCTD)\u2010based deconvolution using a published non\u2010small cell lung cancer (NSCLC) single\u2010cell atlas were performed. Candidate pathway relevance was assessed in The Cancer Genome Atlas (TCGA) KRAS G12C\u2010mutant lung adenocarcinoma cases, and functional validation was performed using fibroblast\u2013tumor co\u2010culture assays. Spatial analysis identified 18 transcriptionally distinct clusters across 14,351 spots. In this exploratory cohort, metastatic\u2010primary tumors showed descriptive expansion of selected spatial domains and reduction of epithelial\/alveolar\u2010associated regions. Deconvolution suggested reduced AT2\u2010like signals and increased fibroblast\u2010associated features in metastatic\u2010primary tumors. Stepwise filtering of group\u2010level, compartment\u2010level and cluster\u2010supported genes identified a fibroblast\u2010associated extracellular matrix remodeling module consisting of COL1A1, COL1A2, COL3A1, SPARC, POSTN, and VCAN. In TCGA KRAS G12C\u2010mutant lung cancer, VCAN expression correlated with collagen formation, extracellular matrix degradation, and EMT marker signatures. In\u00a0vitro, VCAN\u2010overexpressing MRC\u20105 fibroblasts enhanced H358 invasion without markedly altering short\u2010term proliferation. These exploratory analyses identified a fibroblast\u2010associated extracellular matrix remodeling niche associated with metastatic status in KRAS G12C\u2010mutant lung adenocarcinoma. These preliminary findings support further investigation of primary\u2010tumor stromal reprogramming in larger spatially profiled cohorts and mechanistic models.<\/jats:p>","DOI":"10.1002\/ijc.70764","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:06:31Z","timestamp":1790924791000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Transcriptomic Profiling Reveals a Fibroblast\u2010Associated Extracellular Matrix Niche in\n                    <scp>KRAS G12C<\/scp>\n                    \u2010Mutant Lung Adenocarcinoma Primary Tumors From Patients With Metastasis"],"prefix":"10.1002","author":[{"given":"Honggang","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Oncology Affiliated Hospital 6 of Nantong University, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital  Yancheng China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology Affiliated Hospital 6 of Nantong University, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital  Yancheng China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology Affiliated Hospital 6 of Nantong University, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital  Yancheng China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0972-2712","authenticated-orcid":false,"given":"Shoupeng","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Oncology Affiliated Hospital 6 of Nantong University, The Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng Third People's Hospital  Yancheng China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.lungcan.2023.107293","article-title":"KRAS G12C in Advanced NSCLC: Prevalence, Co\u2010Mutations, and Testing","volume":"184","author":"Lim T. K. H.","year":"2023","journal-title":"Lung Cancer"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1056\/NEJMoa2103695","article-title":"Sotorasib for Lung Cancers With KRAS p.G12C Mutation","volume":"384","author":"Skoulidis F.","year":"2021","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2204619","article-title":"Adagrasib in Non\u2010Small\u2010Cell Lung Cancer Harboring a KRASG12C Mutation","volume":"387","author":"J\u00e4nne P. A.","year":"2022","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13092053","article-title":"The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities","volume":"13","author":"Neophytou C. M.","year":"2021","journal-title":"Cancers"},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.ccell.2023.02.016","article-title":"The Evolving Tumor Microenvironment: From Cancer Initiation to Metastatic Outgrowth","volume":"41","author":"Visser K. E.","year":"2023","journal-title":"Cancer Cell"},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization and Analysis of Gene Expression in Tissue Sections by Spatial Transcriptomics","volume":"353","author":"St\u00e5hl P. L.","year":"2016","journal-title":"Science"},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1016\/j.ccell.2022.10.008","article-title":"High\u2010Resolution Single\u2010Cell Atlas Reveals Diversity and Plasticity of Tissue\u2010Resident Neutrophils in Non\u2010Small Cell Lung Cancer","volume":"40","author":"Salcher S.","year":"2022","journal-title":"Cancer Cell"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1038\/s41467-020-18794-x","article-title":"Concepts of Extracellular Matrix Remodelling in Tumour Progression and Metastasis","volume":"11","author":"Winkler J.","year":"2020","journal-title":"Nature Communications"},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13143466","article-title":"Extracellular Matrices and Cancer\u2010Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?","volume":"13","author":"Belhabib I.","year":"2021","journal-title":"Cancers"},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","DOI":"10.1002\/ctm2.1515","article-title":"Single\u2010Cell and Spatial Transcriptomics Reveal POSTN+ Cancer\u2010Associated Fibroblasts Correlated With Immune Suppression and Tumour Progression in Non\u2010Small Cell Lung Cancer","volume":"13","author":"Chen C.","year":"2023","journal-title":"Clinical and Translational Medicine"},{"key":"e_1_2_11_12_1","unstructured":"10x Genomics \u201cVisium CytAssist Spatial Gene Expression for FFPE\u2014Tissue Preparation Guide \u201d(2024) https:\/\/www.10xgenomics.com\/support\/cytassist\u2010spatial\u2010gene\u2010expression\/documentation\/steps\/tissue\u2010prep\/visium\u2010cyt\u2010assist\u2010spatial\u2010gene\u2010expression\u2010for\u2010ffpe\u2010tissue\u2010preparation\u2010guide."},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial Reconstruction of Single\u2010Cell Gene Expression Data","volume":"33","author":"Satija R.","year":"2015","journal-title":"Nature Biotechnology"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single\u2010Cell Data","volume":"177","author":"Stuart T.","year":"2019","journal-title":"Cell"},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41587-021-00830-w","article-title":"Robust Decomposition of Cell Type Mixtures in Spatial Transcriptomics","volume":"40","author":"Cable D. 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The Gene Ontology Consortium","volume":"25","author":"Ashburner M.","year":"2000","journal-title":"Nature Genetics"},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu G.","year":"2012","journal-title":"Omics"},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/s41392-024-01937-7","article-title":"Pre\u2010Metastatic Niche: Formation, Characteristics and Therapeutic Implication","volume":"9","author":"Wang Y.","year":"2024","journal-title":"Signal Transduction and Targeted Therapy"},{"key":"e_1_2_11_19_1","first-page":"587","article-title":"Tumor Metastasis: Mechanistic Insights and Therapeutic Interventions","volume":"2","author":"Liu M.","year":"2021","journal-title":"Medicine Communications"},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","DOI":"10.3390\/cancers17121912","article-title":"Spatial Transcriptomics in Lung Cancer and Pulmonary Diseases: A Comprehensive Review","volume":"17","author":"Kang D. H.","year":"2025","journal-title":"Cancers"},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.adg3840","article-title":"The Extracellular Matrix as Hallmark of Cancer and Metastasis: From Biomechanics to Therapeutic Targets","volume":"16","author":"Sleeboom J. J. F.","year":"2024","journal-title":"Science Translational Medicine"},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41419-024-06697-4","article-title":"Modulating Extracellular Matrix Stiffness: A Strategic Approach to Boost Cancer Immunotherapy","volume":"15","author":"Mai Z.","year":"2024","journal-title":"Cell Death & Disease"},{"key":"e_1_2_11_23_1","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1038\/s41416-024-02671-1","article-title":"Cancer\u2010Associated Fibroblasts Expressing Fibroblast Activation Protein and Podoplanin in Non\u2010Small Cell Lung Cancer Predict Poor Clinical Outcome","volume":"130","author":"Mathieson L.","year":"2024","journal-title":"British Journal of Cancer"},{"key":"e_1_2_11_24_1","doi-asserted-by":"crossref","first-page":"C678","DOI":"10.1152\/ajpcell.00023.2022","article-title":"Matrix Proteoglycans in Tumor Inflammation and Immunity","volume":"323","author":"Deb G.","year":"2022","journal-title":"American Journal of Physiology. Cell Physiology"},{"key":"e_1_2_11_25_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.humpath.2004.10.010","article-title":"Versican in Nonsmall Cell Lung Cancer: Relation to Hyaluronan, Clinicopathologic Factors, and Prognosis","volume":"36","author":"Pirinen R.","year":"2005","journal-title":"Human Pathology"},{"issue":"1","key":"e_1_2_11_26_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1186\/s12967-023-04303-3","article-title":"TGF\u2010\u03b21 Dominates Stromal Fibroblast\u2010Mediated EMT via the FAP\/VCAN Axis in Bladder Cancer Cells","volume":"21","author":"Ping Q.","year":"2023","journal-title":"Journal of Translational Medicine"},{"key":"e_1_2_11_27_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2025.114451","article-title":"Resveratrol Suppresses Growth and VCAN Expression in a Cancer\u2010Associated Fibroblast\u2010Breast Cancer Hybrid Organoid","volume":"153","author":"Shi Y.","year":"2025","journal-title":"International Immunopharmacology"},{"key":"e_1_2_11_28_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/s10555-025-10304-z","article-title":"Spatial Omics: Applications and Utility in Profiling the Tumor Microenvironment","volume":"44","author":"See J. E.","year":"2025","journal-title":"Cancer Metastasis Reviews"},{"key":"e_1_2_11_29_1","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1158\/2767-9764.CRC-23-0548","article-title":"Versican Associates With Tumor Immune Phenotype and Limits T\u2010Cell Trafficking via Chondroitin Sulfate","volume":"4","author":"Hirani P.","year":"2024","journal-title":"Cancer Research Communications"},{"key":"e_1_2_11_30_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1013293","article-title":"PoweREST: Statistical Power Estimation for Spatial Transcriptomics Experiments to Detect Differentially Expressed Genes Between Two Conditions","volume":"21","author":"Shui L.","year":"2025","journal-title":"PLoS Computational Biology"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.70764","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ijc.70764","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.70764","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:06:36Z","timestamp":1790924796000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.70764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":29,"alternative-id":["10.1002\/ijc.70764"],"URL":"https:\/\/doi.org\/10.1002\/ijc.70764","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,2]]},"assertion":[{"value":"2026-05-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"ijc.70764"}}