Publication
Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast-secreted factors through the HGF/C-MET axis
| Summary: | Genetic alterations influence the malignant potential of cancer cells, and so does thetumor microenvironment. Herein, we combined the study of KRAS oncogenic effectsin colorectal cancer cells with the influence of fibroblast-derived factors. Resultsrevealed that mutant KRAS regulates cell fate through both autonomous and nonau-tonomous signaling mechanisms. Specifically, processes such as proliferation andcell-cell aggregation were autonomously controlled by mutant KRAS independentlyof the stimulation with fibroblasts conditioned media. However, cancer cell invasionrevealed to be a KRAS-dependent nonautonomous effect, resulting from the cooper-ation between fibroblast-derived HGF and mutant KRAS regulation of C-METexpression. C-MET downregulation upon KRAS silencing rendered cells less respon-sive to HGF and thus less invasive. Yet, in one cell line, KRAS inhibition triggeredinvasion upon stimulation with fibroblasts conditioned media. Inhibition of PIK3CAoncogene did not promote invasion, thus showing a KRAS-specific effect. Moreover,the invasive capacity also depended on the HGF-C-MET axis. Overall, our studyawards oncogenic KRAS an important role in modulating the response to fibroblast-secreted factors either by promoting or impairing invasion, and depicts the HGF-C-MET axis as a putative therapeutic target to impair the invasive properties of mutantKRAS cancer cells. |
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| Main Authors: | Carvalho, Patrícia Dias |
| Other Authors: | Martins, Flávia; Mendonça, Susana; Ribeiro, Andreia; Machado, Ana Luísa; Carvalho, Joana; Oliveira, Maria José; Velho, Sérgia |
| Subject: | C-MET Colorectal cancer Fibroblasts Invasion KRAS |
| Year: | 2022 |
| Country: | Portugal |
| Document type: | article |
| Access type: | restricted access |
| Associated institution: | Instituto Politécnico do Porto |
| Language: | English |
| Origin: | Repositório Científico do Instituto Politécnico do Porto |
| Summary: | Genetic alterations influence the malignant potential of cancer cells, and so does thetumor microenvironment. Herein, we combined the study of KRAS oncogenic effectsin colorectal cancer cells with the influence of fibroblast-derived factors. Resultsrevealed that mutant KRAS regulates cell fate through both autonomous and nonau-tonomous signaling mechanisms. Specifically, processes such as proliferation andcell-cell aggregation were autonomously controlled by mutant KRAS independentlyof the stimulation with fibroblasts conditioned media. However, cancer cell invasionrevealed to be a KRAS-dependent nonautonomous effect, resulting from the cooper-ation between fibroblast-derived HGF and mutant KRAS regulation of C-METexpression. C-MET downregulation upon KRAS silencing rendered cells less respon-sive to HGF and thus less invasive. Yet, in one cell line, KRAS inhibition triggeredinvasion upon stimulation with fibroblasts conditioned media. Inhibition of PIK3CAoncogene did not promote invasion, thus showing a KRAS-specific effect. Moreover,the invasive capacity also depended on the HGF-C-MET axis. Overall, our studyawards oncogenic KRAS an important role in modulating the response to fibroblast-secreted factors either by promoting or impairing invasion, and depicts the HGF-C-MET axis as a putative therapeutic target to impair the invasive properties of mutantKRAS cancer cells. |
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