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

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

doi:10.1172/jci.insight.148768

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.

Highlights

Neoplastic cells within tumors exhibit distinct genetic, epigenetic, and morphological properties [1]
Side population (SP) cells are enriched for tumor-propagating cells (TPCs) in several types of human sarcoma [22, 23]
Recent evidence in normal tissues suggests that the lineage hierarchy between stem cells and their differentiated progenies may be plastic, where the differentiated cells can acquire stem cell phenotypes under certain conditions, such as during tissue repair [15, 40, 41]

Summary

Introduction

Neoplastic cells within tumors exhibit distinct genetic, epigenetic, and morphological properties [1]. Multiple studies have characterized and targeted TPCs to impede tumor progression in a wide variety of cancer types [10, 11]. Integral to these studies is the assumption that the lineage relationship between TPCs and non-TPCs is unidirectional, where TPCs alone can give rise to non-TPCs. emerging evidence in normal tissues suggests there is substantial lineage plasticity, especially within the context of injury, where differentiated cells can express stem-cell markers and acquire stem cell properties [12, 13]. Whether lineage plasticity exists between TPCs and non-TPCs in sarcomas has not been explored

Methods

Results

Conclusion