Dedifferentiated liposarcomas (DDLPS) are the most frequent high-grade soft tissue sarcoma in adults. Histologically, these tumors are composed of high-grade undifferentiated tumor cells (DD), often showing an abrupt transition from a compartment of well-differentiated adipocytic tumor cells (WD). Tumor cells from both WD and DD compartments are characterized by recurrent MDM2 amplification, but their cellular origin and the molecular mechanisms associated with dedifferentiation are poorly understood.
We performed an integrated molecular analysis of tumors collected from 11 patients undergoing surgery for primary untreated DDLPS. DDLPS tumors were analyzed by single-cell RNA sequencing (scRNAseq) and bulk RNA sequencing on paired WD and DD samples from the same tumors. Results were validated in vitro and in vivo in an additional cohort of human tumors, patient-derived xenografts and DDLPS cell lines.
Through RNA-sequencing of 102,753 individual cells from 11 primary DDLPS lesions, major cell clusters were identified based on unsupervised clustering of gene expression profiles and canonical markers. They include 31 tumor microenvironment clusters and 11 tumor cell clusters. A cluster of tumor cells from the WD compartment is characterized by signatures of early adipocytic progenitors, previously identified as TGFb-dependent, multipotent stromal progenitors. We show that these cells harbor specifically the truncal genomic alterations of the cancer, with further subclonal alterations identifiable in both WD and DD compartments of DDLPS. Furthermore, these cells have multipotent properties and their differentiation towards the adipocytic lineage is inhibited by TGFb. Treatment of DD tumor cells with TGFb inhibitors restores their adipocytic phenotype in vitro and in vivo.
We provide the first single-cell atlas of human DDLPS tumor and microenvironment and identify a population of adipocytic tumor progenitors at the origin of both WD and DD compartments. This study paves the way for a new model of DDLPS oncogenesis and provides rationale for the development of therapeutic strategies based on TGFb inhibition.
The authors.
Les Entreprises Contre le Cancer, Cancéropôle Emergence, Fondation ARC.
All authors have declared no conflicts of interest.