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To elucidate this, paired tumor and adjacent normal mucosa, derived from colon cancer patients\u2019 surgical resections, were decellularized and recellularized with two distinct colon cancer cells, HT-29 or HCT-15. Methods: The matrix impact on cancer stem cell marker expression was evaluated by flow cytometry and qRT-PCR, while transforming growth factor-\u03b2 (TGF-\u03b2) secretion and matrix metalloprotease (MMP) activity were quantified by ELISA and zymography. Results: In contrast to their paired normal counterparts, the tumor decellularized matrices enhanced HT-29 expression of the pluripotency and stemness genes NANOG (p = 0.0117), SOX2 (p = 0.0156), and OCT4 (p = 0.0312) and of the epithelial-to-mesenchymal transition (EMT)-associated transcription factor SNAI1 (p = 0.0156). Notably, no significant differences were found in the expression of SLUG or TGFB on HT-29 or of the six transcripts on HCT-15 cells. HT-29 mRNA alterations were followed by enhanced expression of the stemness-associated receptors cluster of differentiation 44 (CD44), CD133, and CD166 (p = 0.0078), the secretion of TGF-\u03b2 (p = 0.0286), and MMP-2 (p = 0.0081) and MMP-9 (p = 0.0402) proteolysis. To infer the clinical relevance of these findings, we assessed cohort databases and evidenced that patients expressing higher levels of the four stemness-associated genes (NANOG\/SOX2\/OCT4\/SNAI1) had worse overall survival. This study demonstrates that normal and tumor matrices harbor different stemness potential and suggest patient-derived decellularized matrices as an excellent three-dimensional (3D) model to unveil stemness signatures, appointing candidates for future therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26072890","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T07:46:50Z","timestamp":1742802410000},"page":"2890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Patient-Derived Colorectal Cancer Extracellular Matrices Modulate Cancer Cell Stemness Markers"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-5324","authenticated-orcid":false,"given":"\u00c2ngela","family":"Marques-Magalh\u00e3es","sequence":"first","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0748-141X","authenticated-orcid":false,"given":"Sara","family":"Monteiro-Ferreira","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Champalimaud Research, Champalimaud Foundation, 1400-038 Lisbon, Portugal"}]},{"given":"Pedro Amoroso","family":"Can\u00e3o","sequence":"additional","affiliation":[{"name":"Centro Hospitalar Universit\u00e1rio Sa\u0303o Joa\u0303o, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Elisabete","family":"Rios","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Centro Hospitalar Universit\u00e1rio Sa\u0303o Joa\u0303o, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"FMUP\u2014Faculty of Medicine of the University of Porto, Pathology Department, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"\u00c2ngela Margarida","family":"Costa","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2273-2806","authenticated-orcid":false,"given":"Fl\u00e1via","family":"Castro","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}]},{"given":"S\u00e9rgia","family":"Velho","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1076-1343","authenticated-orcid":false,"given":"Joana","family":"Paredes","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"FMUP\u2014Faculty of Medicine of the University of Porto, Pathology Department, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1964-1006","authenticated-orcid":false,"given":"F\u00e1tima","family":"Carneiro","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Centro Hospitalar Universit\u00e1rio Sa\u0303o Joa\u0303o, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"FMUP\u2014Faculty of Medicine of the University of Porto, Pathology Department, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Maria Jos\u00e9","family":"Oliveira","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"FMUP\u2014Faculty of Medicine of the University of Porto, Pathology Department, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Ana Patr\u00edcia","family":"Cardoso","sequence":"additional","affiliation":[{"name":"i3S\u2014Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, 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