Browsing by Author "Machado, Ana Luísa"
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- Influence of KRAS activation in the colorectal cancer immunosurveillance escapePublication . Machado, Ana Luísa; Mendonça, S.; Carvalho, P. Dias; Martins, F.; Oliveira, M. J.; Velho, S.The immune system as a host defense system watches the cell growth and division, eliminating cells with antigens different from those present in healthy cells. However, some transformed cells have the capacity, through various mechanisms, to escape the immune system. Genomic instability and some mutations are pointed as possible mechanisms supporting the immunosurveillance escape, as is the case of KRAS mutation. This oncogenic mutation is present in about 30% of cases of colorectal cancer and confers to the tumor a greater potential for malignancy. It is known that KRAS mutant cancer cells regulate the recruitment, activation, and differentiation of immune cells, promoting tumor evolution by ensuring leakage to the immune system and increasing the proliferative potential. Few evidence highlights an association between a KRAS mutation and myeloid cells, mainly macrophages and neutrophils infiltration. However, the mechanism which determines this interaction remains unclear. Due to the growing knowledge of different immunosuppressive molecules, it became interesting to investigate if there is an alteration in these molecules related to the KRAS activation.
- Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast-secreted factors through the HGF/C-MET axisPublication . Carvalho, Patrícia Dias; Martins, Flávia; Mendonça, Susana; Ribeiro, Andreia; Machado, Ana Luísa; Carvalho, Joana; Oliveira, Maria José; Velho, SérgiaGenetic 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.
- Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS TumorsPublication . Dias Carvalho, Patrícia; Machado, Ana Luísa; Martins, Flávia; Seruca, Raquel; VELHO, SERGIACurrent evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´ aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.