Identifying the role of metabolism in oncogene-induced tumorigenesis

Lead Research Organisation: MRC National Inst for Medical Research

Abstract

It is well known that tumours utilize nutrients differently than normal tissues. This difference may represent an opportunity for new anti-cancer therapeutic strategies. Our previous work showed that the way how tumours use various nutrients depends on which genetic changes they carry. Our goal is to understand how specific genetic lesions determine metabolic changes and nutrient requirement in tumours. In order to do that we will use animal models where tumours can be induced by specific genetic events. We will investigate how metabolism is changed in these tumours. To evaluate the requirement of this changes for tumour development we will use animal models in which the activity of metabolic pathways can be manipulated. Our results should allow us to develop new strategies to treat tumours carrying specific lesions.

Technical Summary

Metabolic changes are thought to provide tumour cells with a proliferation and survival advantage over healthy cells. However, these alterations can also make tumour cells selectively dependent upon certain nutrients and metabolic pathways, making tumour metabolism an attractive therapeutic target. We demonstrated that both the genetic lesions and the tissue of origin are critical factors that determine tumour metabolism. However, the relationship between these factors and their contributions to the metabolic requirements of different tumour types in the context of the whole organism remain largely unknown.
We will use mouse models and stable isotope-based metabolomics approaches to investigate how metabolism is changed in tumours induced by specific pro-tumorigenic events in various mammalian tissues. We will further investigate the requirement of these changes for initiation and progression of oncogene-induced tumorigenesis by using animal models where the expression of enzymes regulating tumor-specific metabolic pathways can be manipulated in tissue-specific and time-specific manners. We will us in vivo and in vitro approaches to understand the molecular mechanisms of tissue-specific regulation of metabolic pathways by different oncogenes as well as how oncogenes induce the metabolic dependence of transformed cells. Finally, we will explore the relationship between oncogenes and metabolic changes in various types of human cancers. Our studies should be able to provide new potential therapeutic targets tailored to specific types of cancers.
 
Title In vivo metabolomics analysis of tumorigenesis 
Description Until recently the changes in metabolism of tumors were mostly judge based on the changes of levels of genes or proteins. Stable isotopes are being used to analyze the activity of various metabolic pathways as well as the destiny of various metabolites. We are developing the methods to analyze the metabolic changes during tumorigenesis using stable isotopes in the settings of the whole organism. We are developing the methods for data collection, analysis and interpretation. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact The information obtained allows for the accurate evaluation of metabolic changes in the settings of the whole organism without the artifacts created by the tissue culture. Moreover the technique allows for the comparison of normal tissue and derived tumors simultaneously. 
 
Title Transgenic mouse lines 
Description The requirement of specific enzyme isoforms in tumorigenesis has been mainly addressed using shRNA techniques or small molecule inhibitors, none of which can insure the absolute specificity of the enzyme activity inhibition. Using transgenic mouse lines allows for absolute specificity of the protein expression and consequently its activity. The lines we are generating also allow for ablating the expression of the specific enzyme isoforms in specific tissue. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact While most of the existing data are obtained in tissue culture conditions, generated mouse models are allowing us to understand the role of specific metabolic pathways in tumorigenesis in the setting of the whole organism close to the situation of the human disease. 
 
Description CDK inhibition and metabolism 
Organisation University of Barcelona
Department Faculty of Biology
Country Spain 
Sector Academic/University 
PI Contribution My group hosted students from collaborator's laboratory. During their stay we created the tools required for the project as well as did some key experiments using the equipment and techniques available in my laboratory. We actively participate in the discussion of the data and planning the experiments.
Collaborator Contribution The collaborator's lab is performing further experiments and analyzing the samples using the equipment available in their laboratory.
Impact The collaboration will result in at least one publication.
Start Year 2013
 
Description Detection of metabolic changes in tumor samples by HR MAS MRS 
Organisation Norwegian University of Science and Technology (NTNU)
Country Norway 
Sector Academic/University 
PI Contribution We are providing samples from normal tissues and tumours from the animals injected with stable isotope tracers.
Collaborator Contribution Employing HR MAS MRS our partners measure and analyse the activity of metabolic pathways in the samples we provide.
Impact The collaboration should result in at least one publication.
Start Year 2014
 
Description Metabolic changes in colorectal tumors 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution We are evaluating the metabolic changes induced by different genetic lesions in in vivo and ex vivo models of colorectal cancers. We are evaluating the requirement of these changes for tumorigenesis in colon and intestine.
Collaborator Contribution They are providing an ex vivo system as well as consulting on methods to manipulate the proteins of interests in this system.
Impact At least one paper is expected
Start Year 2014
 
Description The role of metabolic changes in liver cancer 
Organisation University of California, San Francisco
Country United States 
Sector Academic/University 
PI Contribution Evaluating metabolic changes in oncogene-induced liver tumors. Evaluating metabolic changes in liver tumors in which metabolic enzymes have been manipulated by genetic methods.
Collaborator Contribution Creating models of oncogene-induced liver tumors. Manipulating the expression of proteins of interest in these tumors.
Impact At least one paper is expected.
Start Year 2013