{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:25:47Z","timestamp":1772252747879,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FEDER funds","award":["POCI-01-0145-FEDER-031354"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031354"]}]},{"name":"FEDER funds","award":["SFRH\/BD\/131156\/2017"],"award-info":[{"award-number":["SFRH\/BD\/131156\/2017"]}]},{"name":"FEDER funds","award":["COVID\/BD\/152411\/2022"],"award-info":[{"award-number":["COVID\/BD\/152411\/2022"]}]},{"name":"FEDER funds","award":["SFRH\/BD\/143669\/2019"],"award-info":[{"award-number":["SFRH\/BD\/143669\/2019"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT)","award":["POCI-01-0145-FEDER-031354"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031354"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT)","award":["SFRH\/BD\/131156\/2017"],"award-info":[{"award-number":["SFRH\/BD\/131156\/2017"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT)","award":["COVID\/BD\/152411\/2022"],"award-info":[{"award-number":["COVID\/BD\/152411\/2022"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT)","award":["SFRH\/BD\/143669\/2019"],"award-info":[{"award-number":["SFRH\/BD\/143669\/2019"]}]},{"name":"IPATIMUP","award":["POCI-01-0145-FEDER-031354"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031354"]}]},{"name":"IPATIMUP","award":["SFRH\/BD\/131156\/2017"],"award-info":[{"award-number":["SFRH\/BD\/131156\/2017"]}]},{"name":"IPATIMUP","award":["COVID\/BD\/152411\/2022"],"award-info":[{"award-number":["COVID\/BD\/152411\/2022"]}]},{"name":"IPATIMUP","award":["SFRH\/BD\/143669\/2019"],"award-info":[{"award-number":["SFRH\/BD\/143669\/2019"]}]},{"name":"FCT","award":["POCI-01-0145-FEDER-031354"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031354"]}]},{"name":"FCT","award":["SFRH\/BD\/131156\/2017"],"award-info":[{"award-number":["SFRH\/BD\/131156\/2017"]}]},{"name":"FCT","award":["COVID\/BD\/152411\/2022"],"award-info":[{"award-number":["COVID\/BD\/152411\/2022"]}]},{"name":"FCT","award":["SFRH\/BD\/143669\/2019"],"award-info":[{"award-number":["SFRH\/BD\/143669\/2019"]}]},{"name":"FCT","award":["POCI-01-0145-FEDER-031354"],"award-info":[{"award-number":["POCI-01-0145-FEDER-031354"]}]},{"name":"FCT","award":["SFRH\/BD\/131156\/2017"],"award-info":[{"award-number":["SFRH\/BD\/131156\/2017"]}]},{"name":"FCT","award":["COVID\/BD\/152411\/2022"],"award-info":[{"award-number":["COVID\/BD\/152411\/2022"]}]},{"name":"FCT","award":["SFRH\/BD\/143669\/2019"],"award-info":[{"award-number":["SFRH\/BD\/143669\/2019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Understanding how mutant KRAS signaling is modulated by exogenous stimuli is of utmost importance to elucidate resistance mechanisms underlying pathway inhibition failure, and to uncover novel therapeutic targets for mutant KRAS patients. Hence, aiming at perceiving KRAS-autonomous versus -non autonomous mechanisms, we studied the response of two mutant KRAS colorectal cancer cell lines (HCT116 and LS174T) upon KRAS silencing and treatment with rhTGF\u03b21-activated fibroblasts secretome. A proteomic analysis revealed that rhTGF\u03b21-activated fibroblast-secreted factors triggered cell line-specific proteome alterations and that mutant KRAS governs 43% and 38% of these alterations in HCT116 and LS174T cells, respectively. These KRAS-dependent proteins were localized and displayed molecular functions that were common to both cell lines (e.g., extracellular exosome, RNA binding functions). Moreover, 67% and 78% of the KRAS-associated proteome of HCT116 and LS174T cells, respectively, was controlled in a KRAS-non-autonomous manner, being dependent on fibroblast-secreted factors. In HCT116 cells, KRAS-non-autonomously controlled proteins were mainly involved in proteoglycans in cancer, p53, and Rap1 signaling pathways; whereas in LS174T cells, they were associated with substrate adhesion-dependent cell-spreading and involved in metabolic processes. This work highlights the context-dependency of KRAS-associated signaling and reinforces the importance of integrating the tumor microenvironment in the study of KRAS-associated effects.<\/jats:p>","DOI":"10.3390\/cells11131988","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T21:55:19Z","timestamp":1655848519000},"page":"1988","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mutant KRAS-Associated Proteome Is Mainly Controlled by Exogenous Factors"],"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,  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, R. Jorge de Viterbo Ferreira 228, 4050-313 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,  University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, Faculty of Medicine, University of Porto (FMUP), Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9743-438X","authenticated-orcid":false,"given":"Joana","family":"Carvalho","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,  University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 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,  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, 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,  University of Porto (IPATIMUP), Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1242\/jcs.182873","article-title":"RAS isoforms and mutations in cancer at a glance","volume":"129","author":"Hobbs","year":"2016","journal-title":"J. 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