Sustained activation of notch signaling maintains tumor-initiating cells in a murine model of liposarcoma

Abstract

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.

Keywords: Adipose tissue; Cancer stem cells; Clustered regularly interspaced short palindromic repeats (CRISPR); Dedifferentiation; Transplantation; Tumor heterogeneity.