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mutations have been shown to extend their oncogenic effects beyond the cancer cell, influencing the tumor microenvironment. Herein, we studied the impact of mutant KRAS on the modulation of the pro-tumorigenic properties of cancer-associated fibroblasts (CAFs), including \u03b1-SMA expression, TGF\u03b21 and HGF production, extracellular matrix components and metalloproteinases expression as well as collagen contraction and migration capacities. To do so, CCD-18Co normal-like colon fibroblasts were challenged with conditioned media from control and KRAS silenced colorectal cancer (CRC) cells. Our results showed that the mutant KRAS CRC cell-secreted factors were capable of turning normal-like fibroblasts into CAF-like by modulating the \u03b1-SMA expression, TGF\u03b21 and HGF production and migration capacity. Oncogenic KRAS played a secondary role as its silencing did not completely impair the capacity of CRC cells to modulate most of the fibroblast properties analyzed. In summary, our work suggests that mutant KRAS does not play a major role in controlling the CRC cell-secreted factors that modulate the behavior of fibroblasts. The fact that CRC cells retain the capacity to modulate the pro-tumorigenic features of fibroblasts independently of KRAS silencing is likely to negatively impact their response to KRAS inhibitors, thus standing as a putative mechanism of resistance to KRAS inhibition with potential therapeutical relevance.<\/jats:p>","DOI":"10.3390\/cells11162490","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T05:43:57Z","timestamp":1660196637000},"page":"2490","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Modulation of Fibroblast Phenotype by Colorectal Cancer Cell-Secreted Factors Is Mostly Independent of Oncogenic KRAS"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8110-8157","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Dias Carvalho","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9566-4026","authenticated-orcid":false,"given":"Susana","family":"Mendon\u00e7a","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5773-2881","authenticated-orcid":false,"given":"Fl\u00e1via","family":"Martins","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0724-0272","authenticated-orcid":false,"given":"Maria Jos\u00e9","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Institute of Biomedical Engineering (INEB), University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal"}]},{"given":"S\u00e9rgia","family":"Velho","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade (i3S), Rua Alfredo Allen 208, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41392-021-00780-4","article-title":"KRAS mutation: From undruggable to druggable in cancer","volume":"6","author":"Huang","year":"2021","journal-title":"Signal Transduct. 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