Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma
Yuning Jackie Tang, Vijitha Puviindran, Yu Xiang, Yasuhito Yahara, Hongyuan Zhang, Puviindran Nadesan, Yarui Diao, David G. Kirsch, Benjamin A. Alman
Yuning Jackie Tang, Vijitha Puviindran, Yu Xiang, Yasuhito Yahara, Hongyuan Zhang, Puviindran Nadesan, Yarui Diao, David G. Kirsch, Benjamin A. Alman
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Research Article Oncology

Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma

Abstract

Sarcomas contain a subpopulation of tumor-propagating cells (TPCs) with enhanced tumor-initiating and self-renewal properties. However, it is unclear whether the TPC phenotype in sarcomas is stable or a dynamic cell state that can derive from non-TPCs. In this study, we utilized a mouse model of undifferentiated pleomorphic sarcoma (UPS) to trace the lineage relationship between sarcoma side population (SP) cells that are enriched for TPCs and non-SP cells. By cotransplanting SP and non-SP cells expressing different endogenous fluorescent reporters, we show that non-SP cells can give rise to SP cells with enhanced tumor-propagating potential in vivo. Lineage trajectory analysis using single-cell RNA sequencing from SP and non-SP cells supports the notion that non-SP cells can assume the SP cell phenotype de novo. To test the effect of eradicating SP cells on tumor growth and self-renewal, we generated mouse sarcomas in which the diphtheria toxin receptor is expressed in the SP cells and their progeny. Ablation of the SP population using diphtheria toxin did not impede tumor growth or self-renewal. Altogether, we show that the sarcoma SP represent a dynamic cell state and targeting TPCs alone is insufficient to eliminate tumor progression.

Authors

Yuning Jackie Tang, Vijitha Puviindran, Yu Xiang, Yasuhito Yahara, Hongyuan Zhang, Puviindran Nadesan, Yarui Diao, David G. Kirsch, Benjamin A. Alman

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Figure 4

Cotransplantation and ablation of SP cells in vivo.

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Cotransplantation and ablation of SP cells in vivo. (A) Schematic of cot...
(A) Schematic of cotransplantation and genetic ablation of SP cells expressing diphtheria toxin receptor (DTR) gene. (B) FACS gating scheme to sort for non-SP cells from KPCC tumors and SP cells from KP-DTR tumors for cotransplantation (n = 4). (C) FACS gating of SP and non-SP cells after the tumors are treated with diphtheria toxin (DT) or PBS. (D) The relative expression of the DTR gene for tumors treated with DT compared with tumors treated with 1X PBS. Each symbol represent tumors from a cotransplanted mouse. Triangles represent mice with undetectable DTR expression (*P < 0.05, 2-tailed Student’s t test). Error bars represent mean ± SEM. (E) FACS analysis of mean SP cells expressing fluorescent reporters in cotransplanted tumors after DT or PBS treatment. Each dot represents the mean percentage of fluorescent SP cells from each set of cotransplantation experiments (n ≥ 3 for each set). Error bars represent mean ± SEM.