Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Nadège Gruel, Chloé Quignot, Laëtitia Lesage, Sophie El Zein, Sylvie Bonvalot, Dimitri Tzanis, Khadija Ait Rais, Fabien Quinquis, Bastien Manciot, Julien Vibert, Nadine El Tannir, Ahmed Dahmani, Héloïse Derrien, Didier Decaudin, Ivan Bièche, Laura Courtois, Odette Mariani, Laëtitia K. Linares, Laurie Gayte, Sylvain Baulande, Joshua J. Waterfall, Olivier Delattre, Gaëlle Pierron and Sarah Watson ()
Additional contact information
Nadège Gruel: Institut Curie Research Center
Chloé Quignot: Institut Curie Research Center
Laëtitia Lesage: Institut Curie Hospital
Sophie El Zein: Institut Curie Hospital
Sylvie Bonvalot: Institut Curie Hospital
Dimitri Tzanis: Institut Curie Hospital
Khadija Ait Rais: Institut Curie Hospital
Fabien Quinquis: Institut Curie Hospital
Bastien Manciot: Institut Curie Research Center
Julien Vibert: Institut Curie Research Center
Nadine El Tannir: Institut Curie Research Center
Ahmed Dahmani: PSL Research University, Institut Curie Research Center
Héloïse Derrien: PSL Research University, Institut Curie Research Center
Didier Decaudin: PSL Research University, Institut Curie Research Center
Ivan Bièche: Institut Curie Hospital
Laura Courtois: Institut Curie Hospital
Odette Mariani: Institut Curie Hospital
Laëtitia K. Linares: Université de Montpellier
Laurie Gayte: Université de Montpellier
Sylvain Baulande: PSL Research University, Institut Curie
Joshua J. Waterfall: Institut Curie Research Center
Olivier Delattre: Institut Curie Research Center
Gaëlle Pierron: Institut Curie Hospital
Sarah Watson: Institut Curie Research Center

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52067-1

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