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2020)","award":["10.54499\/2021.01550.CEECIND\/CP1663\/CT0012"],"award-info":[{"award-number":["10.54499\/2021.01550.CEECIND\/CP1663\/CT0012"]}]},{"name":"Norte Portugal Regional Operational Programme (NORTE 2020)","award":["10.54499\/2022.05346.PTDC"],"award-info":[{"award-number":["10.54499\/2022.05346.PTDC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Colorectal cancer (CRC) responses to KRAS-targeted inhibition have been limited due to low response rates, the mechanisms of which remain unknown. Herein, we explored the cancer-associated fibroblasts (CAFs) secretome as a mediator of resistance to KRAS silencing. CRC cell lines HCT15, HCT116, and SW480 were cultured either in recommended media or in conditioned media from a normal colon fibroblast cell line (CCD-18Co) activated with rhTGF-\u03b21 to induce a CAF-like phenotype. The expression of membrane stem cell markers was analyzed by flow cytometry. Stem cell potential was evaluated by a sphere formation assay. RNAseq was performed in KRAS-silenced HCT116 colonospheres treated with either control media or conditioned media from CAFs. Our results demonstrated that KRAS-silencing up-regulated CD24 and down-regulated CD49f and CD104 in the three cell lines, leading to a reduction in sphere-forming efficiency. However, CAF-secreted factors restored stem cell marker expression and increased stemness. RNA sequencing showed that CAF-secreted factors up-regulated genes associated with pro-tumorigenic pathways in KRAS-silenced cells, including KRAS, TGF\u03b2, NOTCH, WNT, MYC, cell cycle progression and exit from quiescence, epithelial-mesenchymal transition, and immune regulation. Overall, our results suggest that resistance to KRAS-targeted inhibition might derive not only from cell-intrinsic causes but also from external elements, such as fibroblast-secreted factors.<\/jats:p>","DOI":"10.3390\/cancers16142595","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T12:20:38Z","timestamp":1721650838000},"page":"2595","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Fibroblasts Promote Resistance to KRAS Silencing in Colorectal Cancer Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9566-4026","authenticated-orcid":false,"given":"Susana Mendon\u00e7a","family":"Oliveira","sequence":"first","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"FMUP\u2014Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"ESS|P.PORTO\u2014Escola Superior de Sa\u00fade, Instituto Polit\u00e9cnico do Porto, Rua Dr. Ant\u00f3nio Bernardino de Almeida 400, 4200-072 Porto, Portugal"}]},{"given":"Patr\u00edcia Dias","family":"Carvalho","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7312-0589","authenticated-orcid":false,"given":"Andr\u00e9","family":"Serra-Roma","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]},{"given":"Patr\u00edcia","family":"Oliveira","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6539-6649","authenticated-orcid":false,"given":"Andreia","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9743-438X","authenticated-orcid":false,"given":"Joana","family":"Carvalho","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]},{"given":"Fl\u00e1via","family":"Martins","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"FMUP\u2014Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"given":"Ana Lu\u00edsa","family":"Machado","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"FMUP\u2014Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"ESS|P.PORTO\u2014Escola Superior de Sa\u00fade, Instituto Polit\u00e9cnico do Porto, Rua Dr. Ant\u00f3nio Bernardino de Almeida 400, 4200-072 Porto, Portugal"}]},{"given":"Maria Jos\u00e9","family":"Oliveira","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"FMUP\u2014Faculdade de Medicina da Universidade do Porto, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar, Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"INEB\u2014Instituto Nacional de Engenharia Biom\u00e9dica, Universidade do Porto, Rua do Campo Alegre 823, 4150-177 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7104-8234","authenticated-orcid":false,"given":"S\u00e9rgia","family":"Velho","sequence":"additional","affiliation":[{"name":"i3S\u2014Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"IPATIMUP\u2014Instituto de Patologia e Imunologia Molecular, Universidade do Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12153","DOI":"10.3390\/ijms131012153","article-title":"Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer","volume":"13","author":"Arrington","year":"2012","journal-title":"Int. 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