CD24: a new therapeutic target in dedifferentiated liposarcoma
Dedifferentiated liposarcomas (DDLPS) is the most frequent high-grade soft tissue sarcoma in adults, and characterized by a significant risk of metastatic relapse and death. New active systemic therapies are urgently needed, as conventional cytotoxic chemotherapy and immunotherapy provide limited benefit for patients with advanced disease. Using single-cell RNA sequencing (scRNAseq) on a cohort of primary human DDLPS, we identified a population of DDLPS tumor cells characterized by the overexpression of a gene signature related to invasion and metastases, among which CD24 was the top overexpressed gene. CD24 has previously been shown in other malignancies to have protumorigenic functions such as promoting immune escape and metastases development. Our preliminary data show that CD24 interacts with specific cells from DDLPS tumor microenvironment including myeloid cells and endothelial cells. Our hypothesis is that CD24 overexepression in DDLPS could represent an oncogenic mechanism driving tumor progression, metastatic development and immune escape, and could thus represent a new therapeutic opportunity. The main objective of this proposal is to decipher the functions of CD24 in the context of DDLPS, and to evaluate the impact of its targeting as new therapeutic strategy. For this purpose, we will: 1) Generate relevant experimental models based on the genetic inactivation of CD24 in available DDLPS cell lines to evaluate the consequences of CD24 inactivation on tumor cell phenotype, immune response, pro-angiogenic and invasion properties both in vitro and in vivo; 2) Evaluate the prognostic impact of CD24 expression in a cohort of DDLPS tumors and correlate CD24 expression with various clinical and pathological features; 3) Study the antitumoral activity of selected monoclonal antibodies targeting CD24 in cell lines, primary cultures from human tumors and already available patient-derived xenografts. In summary, we will combine cell biology, genetics, molecular biology, bioinformatics and in vivo experiments to address the role of CD24 in DDLPS oncogenesis. This approach will provide essential information for the prognostic stratification of patients and may lead to new therapeutic developments based on CD24 inhibition in DDLPS. The interdisciplinary expertise of our team, the integrative approach of our project, our access to unique clinical specimens, and our robust preliminary data provide a high potential to transform our understanding of DDLPS oncogenesis and the clinical management of DDLPS patients.