Final Activity Report Summary - AURORAA_MOUSE_MODELS (Aurora A mouse models: new tools for the study of mitosis deregulation in cancer)
Cell cycle alterations are one of the common characteristics of all kind of human cancers. So far, most of cell cycle that have been associated with tumours target key regulators of the initial stages of the cell cycle (G1 progression and the G1/S transition). However, since most mammalian cells proliferate without most of them their use as therapeutic targets is not clear. Much less is known about the involvement of other cell cycle regulators, which alterations target specific cell cycle regulators involved either in the centrosome cycle or in sister-chromatid separation, two cellular processes that are critical for a proper. Therefore, the research in this field will be highly significant taking into account that cell cycle is deregulated in most human tumours and the search for good molecular targets for cancer therapy is still open.
Our main goal is to analyse the function of Aurora kinases in cell cycle regulation and tumourigenesis using genetically engineered mouse models. Aurora kinase family is one of the most relevant groups of kinases that drive mitotic progression, take care of the genomic stability and confer susceptibility to oncogenic transformation processes. Besides the importance of this family of kinases, little is mechanistically known about their role in both normal and tumoural cells. To solve these open questions we decided to generate and characterise both gain-of-function and loss-of-function mouse models for Aurora kinases.
Our specific objectives were the following:
1. To generate and characterise three genetically-modified cKO mouse models to conditionally eliminate the Aurora A, B and C expression. These models will allow us to analyse the role of each of the Aurora kinase family members both in cell function and in vivo.
2. To generate and characterise an Aurora A transgenic mouse model to over-express in mammary tissue Aurora A cDNA either wild type or carrying S50D/R362A mutation that make this kinase resistant to its protein degradation at the end of mitosis. This model will allow us to better understand the role of Aurora A altered expression in tumourigenesis.
3. The generation of new genetically modified, conditional, kinase-dead (cKI) mouse models for Aurora A and B, which will allow us to switch from the wild type form of these kinases to the corresponding inactive ones. We will compare these models with those from objective 1 to understand the differences between removing the protein and inactivating the kinase function in vivo or in vitro.
During the two years of the Re-Integration Marie Curie Fellowship, we have initiated the generation and characterisation of these loss-of-function and gain-of-function mouse models for Aurora kinases that are showing us how important these kinases are for mouse development and tumourigenesis. Moreover, these mouse models will provide essential reagents that will allow us in the near future (i) to generate an Aurora-less mouse, which will be crucial for the study of the role of Aurora kinases in mitosis and cancer; (ii) to generate and study mice in which Aurora A is over-expressed at the protein level in mammary tissue, a phenotype that has been already reported in human breast cancer; and (iii), using the potent tool of the cKI mouse models, to validate the use of Aurora inhibitors in antitumoural therapies.
Finally, we would like to point out that this project is mostly based on in vivo models for validation in cancer therapy. These pre-clinical models are necessary to fill in the gap between in vitro systems and clinical trials and are the only way to validate molecular targets for cancer therapy in vivo. As far as we know, the present project is the only in-progress project in which Aurora mouse models are being generated to validate its role in cancer and to be used in the generation of new antitumoural drugs.
Our main goal is to analyse the function of Aurora kinases in cell cycle regulation and tumourigenesis using genetically engineered mouse models. Aurora kinase family is one of the most relevant groups of kinases that drive mitotic progression, take care of the genomic stability and confer susceptibility to oncogenic transformation processes. Besides the importance of this family of kinases, little is mechanistically known about their role in both normal and tumoural cells. To solve these open questions we decided to generate and characterise both gain-of-function and loss-of-function mouse models for Aurora kinases.
Our specific objectives were the following:
1. To generate and characterise three genetically-modified cKO mouse models to conditionally eliminate the Aurora A, B and C expression. These models will allow us to analyse the role of each of the Aurora kinase family members both in cell function and in vivo.
2. To generate and characterise an Aurora A transgenic mouse model to over-express in mammary tissue Aurora A cDNA either wild type or carrying S50D/R362A mutation that make this kinase resistant to its protein degradation at the end of mitosis. This model will allow us to better understand the role of Aurora A altered expression in tumourigenesis.
3. The generation of new genetically modified, conditional, kinase-dead (cKI) mouse models for Aurora A and B, which will allow us to switch from the wild type form of these kinases to the corresponding inactive ones. We will compare these models with those from objective 1 to understand the differences between removing the protein and inactivating the kinase function in vivo or in vitro.
During the two years of the Re-Integration Marie Curie Fellowship, we have initiated the generation and characterisation of these loss-of-function and gain-of-function mouse models for Aurora kinases that are showing us how important these kinases are for mouse development and tumourigenesis. Moreover, these mouse models will provide essential reagents that will allow us in the near future (i) to generate an Aurora-less mouse, which will be crucial for the study of the role of Aurora kinases in mitosis and cancer; (ii) to generate and study mice in which Aurora A is over-expressed at the protein level in mammary tissue, a phenotype that has been already reported in human breast cancer; and (iii), using the potent tool of the cKI mouse models, to validate the use of Aurora inhibitors in antitumoural therapies.
Finally, we would like to point out that this project is mostly based on in vivo models for validation in cancer therapy. These pre-clinical models are necessary to fill in the gap between in vitro systems and clinical trials and are the only way to validate molecular targets for cancer therapy in vivo. As far as we know, the present project is the only in-progress project in which Aurora mouse models are being generated to validate its role in cancer and to be used in the generation of new antitumoural drugs.