Cellular origin and clonal evolution of human dedifferentiated liposarcoma
Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing, DNA sequencing, in situ multiplex immunofluorescence and functional assays in paired WD and DD components from primary DDLPS tumors, we characterize the cellular heterogeneity of DDLPS tumor and micro-environment. We identify a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β-high immunosuppressive tumor micro-environment.
Authors
- Dimitri Tzanis (ORCID: https://orcid.org/0000-0001-8090-1391)
- Joshua J. Waterfall (ORCID: https://orcid.org/0000-0002-3762-5050)
- Julien Vibert (ORCID: https://orcid.org/0000-0002-2370-3302)
- Khadija Aït Raïs
- Olivier Delattre (ORCID: https://orcid.org/0000-0002-8730-2276)
- Laëtitia K. Linares (ORCID: https://orcid.org/0000-0003-1661-2119)
- Sarah Watson (ORCID: https://orcid.org/0000-0003-4534-8783)
- Ivan Bièche (ORCID: https://orcid.org/0000-0002-2430-5429)
- Nadège Gruel (ORCID: https://orcid.org/0000-0001-6915-8082)
- Laurie Gayte
- Sylvie Bonvalot (ORCID: https://orcid.org/0000-0001-9726-9732)
- Odette Mariani (ORCID: https://orcid.org/0000-0002-3517-4399)
- Fabien Quinquis
- Sophie El Zein (ORCID: https://orcid.org/0000-0001-6630-0020)
- Héloïse Derrien (ORCID: https://orcid.org/0009-0004-0956-3958)
- Chloé Quignot (ORCID: https://orcid.org/0000-0001-8504-232X)
- Sylvain Baulande (ORCID: https://orcid.org/0000-0003-3104-1684)
- Gaëlle Pierron (ORCID: https://orcid.org/0000-0002-2536-7680)
- Laëtitia Lesage (ORCID: https://orcid.org/0000-0001-8592-2482)
- Didier Decaudin
- Laura Courtois
- Nadine El Tannir
- Bastien Manciot
- Ahmed Dahmani (ORCID: https://orcid.org/0000-0002-8770-120X)
Institutions
- Inserm (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Institut de Recherche en Cancérologie de Montpellier (FR)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-12
- DOI
- https://doi.org/10.1038/s41467-024-52067-1
- Citations
- 17
- Primary Topic
- Sarcoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 7.12
Funders
- Equipex
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- Groupement des Entreprises Françaises dans la lutte contre le Cancer