Cells in a tumor are heterogeneous, often including a small number of tumor-initiating cells (TICs) and the majority of cancerous and non-cancerous cells. We have previously reported that constitutive activation of Notch signaling in adipocytes of mice leads to dedifferentiated liposarcoma (DDLPS), an aggressive liposarcoma (LPS) with no effective treatment. Here, we explored the role of Notch signaling in cellular heterogeneity of LPS. We performed serial transplantations to enrich for TICs, and derived cells exhibiting sustained Notch activation (mLPS1 cells) and cells with normal Notch activity (mLPS2 cells). Both mLPS1 and mLPS2 cells proliferated rapidly, and neither exhibited contact inhibition. However, only the mLPS1 cells exhibited tumorigenicity and gave rise to LPS upon engraftment into mice. The mLPS1 cells also highly expressed markers of cancer stem cells (Cd133), mesenchymal stem cells (Cd73, Cd90, Cd105, Dlk1) and the long non-coding RNA Rian. By contrast, the mLPS2 cells accumulated lipid droplets and expressed mature adipocyte markers when induced to differentiate. Most importantly, CRISPR-mediated disruption of Notch abrogated the tumorigenic properties of mLPS1 cells. These results reveal a key role of Notch signaling in maintaining TICs in LPS.

肿瘤中的细胞是异质的，通常包括少量的肿瘤起始细胞 (TIC) 和大多数癌细胞和非癌细胞。我们之前曾报道过，小鼠脂肪细胞中 Notch 信号的组成性激活会导致去分化脂肪肉瘤 (DDLPS)，这是一种没有有效治疗的侵袭性脂肪肉瘤 (LPS)。在这里，我们探讨了 Notch 信号在 LPS 细胞异质性中的作用。我们进行了连续移植以富集 TIC，以及表现出持续 Notch 激活的衍生细胞（mLPS1 细胞）和具有正常 Notch 活性的细胞（mLPS2 细胞）。mLPS1 和 mLPS2 细胞增殖迅速，均未表现出接触抑制。然而，只有 mLPS1 细胞表现出致瘤性并在植入小鼠后产生 LPS。Cd133)、间充质干细胞（Cd73、Cd90、Cd105、Dlk1）和长链非编码 RNA Rian。相比之下，mLPS2 细胞在诱导分化时会积累脂滴并表达成熟的脂肪细胞标记物。最重要的是，CRISPR 介导的 Notch 破坏消除了 mLPS1 细胞的致瘤特性。这些结果揭示了 Notch 信号在维持 LPS 中的 TIC 中的关键作用。