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Even though salivary gland carcinomas (SGCs) display a range of tumor cell differentiation and distinct extracellular matrices, their ECM landscape has not been characterized in depth. The ECM composition of 89 SGC primaries, 14 metastases, and 25 normal salivary gland tissues was assessed using deep proteomic profiling. Machine learning algorithms and network analysis were used to detect tumor groups and protein modules that explain specific ECM landscapes. Multimodal <jats:italic>in situ<\/jats:italic> studies to validate exploratory findings and to infer a putative cellular origin of ECM components were applied. We revealed two fundamental SGC ECM classes which align with the presence or absence of myoepithelial tumor differentiation. We describe the SGC ECM through three biologically distinct protein modules that are differentially expressed across ECM classes and cell types. The modules have a distinct prognostic impact on different SGC types. Since targeted therapy is rarely available for SGC, we used the proteomic expression profile to identify putative therapeutic targets. In summary, we provide the first extensive inventory of ECM components in SGC, a difficult\u2010to\u2010treat disease that encompasses tumors with distinct cellular differentiation. \u00a9 2023 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6071","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T23:41:53Z","timestamp":1677109313000},"page":"148-164","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The extracellular matrix landscape in salivary gland carcinomas is defined by cellular differentiation via expression of three distinct protein modules"],"prefix":"10.1002","volume":"260","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6366-2285","authenticated-orcid":false,"given":"Christoph","family":"Arolt","sequence":"first","affiliation":[{"name":"Institute of Pathology, Medical Faculty University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology MALDI Imaging and Innovative Biophotonics, Jena University Hospital  Jena Germany"},{"name":"Department of Otorhinolaryngology, Head and Neck Surgery Jena University Hospital  Jena Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Nachtsheim","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Medical Faculty University of Cologne  Cologne 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