INSERM U830, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, Institut Curie Research Center, Paris, France.
Department of Translational Research, Institut Curie Research Center, Paris, France.
Nat Commun. 2024 Sep 12;15(1):7941. doi: 10.1038/s41467-024-52067-1.
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.
去分化脂肪肉瘤（DDLPS）是最常见的高级软组织肉瘤亚型。它的特征是存在未分化的肿瘤细胞成分和分化良好的脂肪性肿瘤细胞成分。去分化（DD）和分化良好（WD）成分均表现出 MDM2 扩增，但它们的细胞起源仍不清楚。通过对原发性 DDLPS 肿瘤的 WD 和 DD 成分进行单细胞 RNA 测序、DNA 测序、原位多重免疫荧光和功能检测，我们对 DDLPS 肿瘤及其微环境的细胞异质性进行了描述。我们鉴定出一群肿瘤脂肪细胞干细胞（ASC），它们与在白色脂肪组织中发现的脂肪基质祖细胞具有惊人的相似性。我们表明，肿瘤 ASC 具有 WD 和 DD 成分的原始基因组改变，这表明它们都来源于这些祖细胞的克隆进化。最后，我们表明 DD 肿瘤细胞保持了 ASC 的重要生物学特性，包括多能性，并且它们的成脂特性被 TGF-β 高免疫抑制性肿瘤微环境所抑制。
