Research
Metabolism and sarcomas : Laetitia Linares

Background: Sarcomas are rare tumors developing in the connective tissue, with about 3000 new cases per year in France. There are many types of sarcomas.
15% of them are represented by liposarcomas. In particular, a genetic abnormality corresponding to the amplification of the MDM2 gene is observed in almost 100% of cases of liposarcomas making it a therapeutic target of choice. Its role in the development of liposarcomas was studied and seemed to be related to its interaction with the genome keeper, p53. However, the various studies that have targeted this interaction have been disappointing with little impact on tumor growth, suggesting that its role is elsewhere.
We have identified this other role, which is related to amino acid metabolism. Part of our work is to explore in detail this new metabolic role of MDM2 and to evaluate the development of new therapeutic strategies to combat liposarcomas. Currently, there is no effective treatment for liposarcomas, and diagnosis is long and difficult. A better understanding of the role of the MDM2 protein on cell metabolism and the development of liposarcomas is a major challenge in identifying new diagnostic and therapeutic strategies. We were able to show that targeting MDM2 and serine metabolism was a model of choice in the fight against liposarcoma. Our objectives are to improve the understanding of the development of this tumor and to identify factors that play an important role in their occurrence.
Our data on liposarcomas thus open up interesting perspectives for the study of metabolism in the occurrence of sarcomas. We seek to deepen the notion that metabolism could play a key role in the development of sarcomas.
Objectives: On the basis of our data, the team’s project aims to better develop our understanding of metabolism on the development of liposarcoma and evaluate whether this represents interesting new targets for new therapeutic strategies. 

Our main objectives are:

1)  Tumor and Environment
The study of tumor development in vivo is to be taken in a systemic context. Indeed, the impact of cancer cells on their environment (both locally and remotely) is known to promote malignancy and chemoresistance. Understanding the interactions between cancer cells and environmental metabolism is essential for combining targeted metabolism therapies with chemotherapies and using these environmental phenomena as tumor markers.
    
2) New therapeutic strategies in liposarcoma involving the metabolic activities of MDM2: An important part of this project will evaluate the interest of new therapeutic strategies targeting the metabolic functions of MDM2. 

3)  New diagnostic and prognostic strategies
Liposarcomas can be difficult to distinguish from benign fatty tumors and undifferentiated sarcomas. Molecular analyses, based on the detection of MDM2 gene amplification by FISH (currently the “gold standard”), are performed on a tumour biopsy, but this diagnosis is invasive and time-consuming, delaying the management of patients with liposarcoma.
Based on our new findings showing the role of metabolism in the development of liposarcomas, we propose to identify new biological markers that would indicate the presence of the disease. This project is based on the complementary expertise provided by clinicians, researchers and biostatisticians in close collaboration.

4)  Other sarcomas and metabolism
We seek to assess the role of metabolism in the development of other sarcomas.