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Parallel to this observation, the specific context-dependent, spatial dynamics of these pathways and their interaction with the tumour microenvironment (TME) remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a spatially resolved analysis of PDAC on a multi-region tissue microarray cohort of 117 curatively resected PDAC specimens consisting of tumour centre (TC), tumour front (TF), and stromal(-predominant) tissue cores each. Protein (ID1, pSMAD2) and mRNA (TGF-A, TGF-B1\/2, BMP4, GREM1) expression were assessed in each tissue compartment by immunohistochemistry and in situ hybridization, respectively, quantified by digital image analysis, and correlated with clinicopathologic features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ID1 was significantly overexpressed in PDAC cells compared to associated stroma (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), while pSMAD2 was largely absent in PDAC cells, but preserved among associated stroma compartments, particularly in TF cores (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04). Higher stromal GREM1 signal correlated with reduced overall tumoural ID1 protein expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.02), and TGF-B2\n                      <jats:sup>high<\/jats:sup>\n                      \/TGF-A\n                      <jats:sup>low<\/jats:sup>\n                      stroma was significantly associated with worse survival (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Intratumoural TGF-B2 was inversely correlated with stromal pSMAD2 expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03) and was associated with lymph node involvement (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.02). FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      regulatory T-cells were significantly reduced in TGF-B2\n                      <jats:sup>high<\/jats:sup>\n                      tumours (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04), while higher tumoural TGF-B1 exhibited a trend towards increased FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      cells (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.08).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our spatial analysis reveals intratumoural heterogeneity of TGF\/BMP signalling and its significance for PDAC progression. Notably, stromal TGF-B2 emerges as a prognostic biomarker, while TGF-B1 and ID1 are implicated in adverse clinical and pathologic features. These findings highlight the importance of TGF\/BMP signalling niches in the TME with implications for PDAC biology and can inform the development of future therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12885-025-14751-3","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T06:42:00Z","timestamp":1755499320000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Spatially resolved analysis of TGF\/BMP signalling in pancreatic ductal adenocarcinoma by digital pathology identifies patient subgroups with adverse outcome"],"prefix":"10.1186","volume":"25","author":[{"given":"Konstantin","family":"Br\u00e4utigam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Zens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Reinhard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Rohrbach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"Leedham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna S.","family":"Wenning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Gloor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor H.","family":"Koelzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Wartenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"issue":"1","key":"14751_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41571-020-0403-1","volume":"18","author":"R Derynck","year":"2021","unstructured":"Derynck R, Turley SJ, Akhurst RJ. 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