Research
Metabolism and sarcomas : Laetitia Linares

Background: Sarcomas are cancers that develop in connective tissues such as fat, muscles, bones, or nerves. They represent a rare form of cancer, accounting for about 2% of cancers diagnosed in adults and 15% in children. Each year, approximately 3,000 new cases of sarcomas are diagnosed in France. Due to their rarity and diversity, sarcomas pose considerable challenges in terms of diagnosis and therapy. Surgical resection, when possible, is considered the primary treatment. It is often associated with neoadjuvant chemotherapy or radiotherapy. In the absence of effective treatments, patients with sarcomas have a relatively low survival rate compared to other types of cancer, hovering around 50%. Liposarcomas develop from fat cells and represent about 15% of all sarcomas. This histological subtype presents a genetic anomaly characterized by an amplification of the MDM2 gene, observed in nearly 100% of cases. This peculiarity makes it a privileged therapeutic target. Initially, its role in the development of liposarcomas seemed to be related to its interaction with the guardian of the genome, the p53 protein. However, various studies targeting this interaction have proven disappointing, showing little effect on tumor growth, suggesting that the role of MDM2 in these sarcomas may be different from initially envisioned. Recently, our team has highlighted another role of MDM2, related to amino acid metabolism. Therefore, part of our work now involves exploring in detail this new metabolic function of MDM2. A better understanding of the role of the MDM2 protein in cellular metabolism and the development of liposarcomas is a major challenge for identifying new diagnostic and therapeutic approaches. Indeed, there is currently no effective treatment for combating liposarcomas, and the diagnosis of this disease is often long and complex. Interestingly, we have shown that targeting MDM2 and serine metabolism represents a promising strategy in the fight against liposarcoma. Thus, our goals are to better understand the development of this tumor and to identify factors playing an important role in their occurrence. Our research on liposarcomas therefore offers interesting prospects for exploring the link between amino acid metabolism and the occurrence of sarcomas. Consequently, we strive to deepen the idea that metabolism could play a key role in the development of these cancers. Objectives: Based on our data, our team is committed to deepening the understanding of the link between amino acid metabolism and the development of liposarcoma, as well as assessing whether this opens up new avenues for innovative therapeutic strategies. Our main objectives are:

1. Tumor and environment

 The study of tumor development in vivo must be approached in a systemic context. Indeed, the impact of cancer cells on their environment (both locally and at a distance) is known to promote malignancy and chemoresistance. Understanding the interactions between cancer cells and environmental metabolism is essential for associating metabolism-targeting therapies with chemotherapy, and for using these environmental phenomena as tumor markers.

2. New therapeutic strategies in liposarcoma involving MDM2 metabolic activities:

An important part of this project is to evaluate the interest of new therapeutic strategies targeting the metabolic functions of MDM2.

3. New diagnostic and prognostic strategies

Distinguishing liposarcomas from benign adipose tumors, undifferentiated sarcomas, as well as adjacent healthy tissues can often pose a diagnostic challenge. Currently, molecular analyses on a tumor biopsy based on the detection of MDM2 gene amplification by FISH are considered the gold standard. However, this diagnostic method is invasive and time-consuming, delaying the management of patients with liposarcoma. In light of our new findings on the role of metabolism in the development of liposarcomas, we propose to develop new biological tests that will ultimately facilitate early diagnosis of the disease. This project relies on the complementary expertise of clinicians, researchers, and biostatisticians working closely together.

4. Other sarcomas and metabolism

We seek to evaluate the role of MDM2 in controlling metabolism related to the development of other sarcomas.