Identification of molecular targets in lung and pituitary gland tumors spontaneously generated in p27-/- and p27CK- mice models
- Principle investigator:
- Oriol Bachs
- Contact details:
The development of human tumors is the consequence of the acquisition of eight biological capabilities including: sustained proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion, reprogramming energy metabolism and evading immune destruction. These capabilities grouped under the concept of “Hallmarks of Cancer” define the main molecular pathways that have to be altered to develop a malignant tumor.
To understand the alterations in these pathways involved in the development of specific types of tumors it is extremely useful to analyze the status of the molecular components of these pathways in tumors spontaneously generated in genetically modified mice harboring a well-defined gene alteration. Some interesting mice models are those affecting the p27Kip1 protein. The p27-/--mice, develop pituitary tumors, lymphomas and spleen and ovarian hyperplasias. The p27CK- -mice, harboring a p27 mutant unable to inhibit Cdks, also develops the mentioned tumors but in addition lung and adrenal tumors.
The aim of our group is to identify the main molecular alterations leading to the development of lung and pituitary tumors in these mice models. We specifically aim to identify pharmacological targets susceptible to be used in anti-cancer treatments.
Our group has reported that p27 regulates transcription and pre-mRNA splicing (Pippa et al., Oncogene, 2011; Perez-Luna et al., Nucleic Acids Research, 2012, in press and unpublished results). We found that p27 associates with specific gene promoters and regulates its expression in collaboration with p130/E2F4 or ETS complexes. Expression microarray analysis performed in MEFs from these p27 mice models allowed us to identify a number of molecular pathways altered in the KO and Knock-in cells potentially involved in the development of tumors. Finally, we observed that the over-expression of these p27-TGs in human tumors is associated with poor survival of patients. To achieve the goals of the project we are working with expression and splicing microarrays, ChIP, ChIP on chip analysis, proteomics, affinity chromatography, immunocytochemistry, Western blotting and other conventional methods of Cell Biology and Biochemistry.
P27, tumor development, lung cancer, pituitary gland tumors, molecular targets. Pharmacological targets
Developing new and highly specific anti-cancer therapies requires a high level of knowledge on the specific molecular pathways altered in each defined type of tumors. The main aim of our group is to acquire high quality information on the molecular alterations in lung and pituitary tumors that could be the main responsible of the tumor induction in defined animal models.
We expect to achieve this knowledge by using high potency expression and splicing microarrays followed by bioinformatic analysis of pathways and the subsequent validation of the functional relevance of the altered molecules. We expect that the person that would incorporate in our team could contribute to the design and planning of the experiments related with this project and also in the development of specific tools for the analysis and validation of the obtained results. We also expect from this person to have the required skills, abilities and knowledge to perform this work
Team strategic objective in IDIBAPS
The concept “Hallmarks of Cancer” defines the main molecular pathways that have to be altered to develop a malignant tumor. The main goal of this Research Group is to identify putative pharmacological targets in these altered pathways that could generate advantages in the anti-cancer treatments. Specifically, we are focusing our attention in identifying pharmacological targets in lung and pituitary gland tumors spontaneously developed in p27-/- - and p27CK- - mice models. Once identified specific pharmacological targets in the animal models its utility in human tumors will be subsequently validated.(Read eligibility criteria)