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ePoster Display

1531P - Multi-omic characterization of dedifferentiated liposarcoma: Towards a new model of oncogenesis?

Date

16 Sep 2021

Session

ePoster Display

Topics

Cancer Biology;  Rare Cancers

Tumour Site

Soft Tissue Sarcomas

Presenters

Sarah Watson

Citation

Annals of Oncology (2021) 32 (suppl_5): S1111-S1128. 10.1016/annonc/annonc712

Authors

S. Watson1, N. Gruel2, J. Vibert2, S. Bonvalot3, S. El Zein4, D. Tzanis5, S. Lameiras6, E. Girard7, M. Galut4, M. Lavigne4, O. Mariani4, S. Baulande6, O. Delattre8, J. Waterfall8

Author affiliations

  • 1 Inserm U830, Institut Curie, 75005 - Paris/FR
  • 2 Inserm U830, Institut Curie, Paris/FR
  • 3 Dept. Surgery, Institut Curie, 75005 - Paris/FR
  • 4 Pathology Dpt, Institut Curie, Paris/FR
  • 5 Surgical Oncology - Sarcomas And Complexe Tumors, Institut Curie, 75005 - Paris/FR
  • 6 Icgex Platform, Institut Curie, Paris/FR
  • 7 Inserm U900, Institut Curie, Paris/FR
  • 8 Research Center, Institut Curie, 75005 - Paris/FR

Resources

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Abstract 1531P

Background

Dedifferentiated liposarcomas (DDLPS) are one of the most frequent sarcoma subtypes, characterized by the coexistence of one low-grade, adipocytic, well-differentiated (WD) component and one high-grade, undifferentiated (DD) component. The molecular mechanisms determining the existence of these two distinct cell populations are poorly understood. We performed a multi-omics characterization of DDLPS to decipher the molecular and micro environmental characteristics of WD and DD components.

Methods

27 patients operated on in our institution for a primary DDLPS were included. For each tumor, two samples were freshly isolated from the WD and the DD components. The transcriptomic and genomic profiles of the tumors were studied by single-cell RNA sequencing (scRNAseq), bulk RNA sequencing, and Whole Exome Sequencing. Control samples included well-differentiated liposarcomas (WDLPS), benign tumors and normal fat.

Results

We show that: 1) The WD and DD components of the same tumors are characterized by distinct microenvironments, with the presence of cytotoxic exhausted T lymphocytes and M2 macrophages predominating in the DD part. 2) WD tumor cells overexpress genes involved in adipocytic differentiation and lipid metabolism, whereas DD cells highly express genes involved in cell proliferation and invasion. 3) scRNAseq data show no intermediate tumor cell population, neither any differentiation trajectory between WD and DD tumor cells. This is further confirmed by genomic analyses showing of low number of common genomic alterations between both compartments. 4) Last, integration of scRNAseq data from all patients shows that the molecular distance between WD and DD components can vary from one tumor to the other, suggesting a variability in the signal of adipocytic maturation arrest at the origin of the DD contingent emergence.

Conclusions

This is the first integrated multi-omics study of a large cohort of DDLPS. We show that the DD tumor component does not derive from the dedifferentiation of WD cells, but instead that both components may derive early from a common adipocytic progenitor. The variability in the divergence signal between tumors may explain the clinical heterogeneity of patients in terms of prognosis and treatment response.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cancéropôle Ile de France, ANR, Sarcoma Foundation of America.

Disclosure

All authors have declared no conflicts of interest.

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