A new immunological 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 a specific gene, later called X was the top overexpressed gene. X has previously been shown in other malignancies to have protumorigenic functions such as promoting immune escape and metastases development. Our preliminary data show that X interacts with specific cells from DDLPS tumor microenvironment. Our hypothesis is that X 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 X 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 X in available DDLPS cell lines to evaluate the consequences of X inactivation on tumor cell phenotype, immune response, pro-angiogenic and invasion properties both in vitro and in vivo; 2) Evaluate the prognostic impact of X expression in a cohort of DDLPS tumors and correlate X expression with various clinical and pathological features; 3) Study the antitumoral activity of selected monoclonal antibodies targeting X 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 X in DDLPS oncogenesis. This approach will provide essential information for the prognostic stratification of patients and may lead to new therapeutic developments based on X 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.