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JAK–STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma

Journal article
Authors Soheila Dolatabadi
Emma Jonasson
Malin Lindén
Bentolhoda Fereydouni
Karin Bäcksten
Malin Nilsson
Anna Martner
Amin Forootan
Henrik Fagman
Göran Landberg
Pierre Åman
Anders Ståhlberg
Published in International Journal of Cancer
Volume 145
Issue 2
Pages 435-449
ISSN 0020-7136
Publication year 2019
Published at Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Pathology
Wallenberg Centre for Molecular and Translational Medicine
Pages 435-449
Language en
Links dx.doi.org/10.1002/ijc.32123
Keywords cancer stem cells, chemotherapy resistance, JAK–STAT signalling, LIF, myxoid liposarcoma, ruxolitinib, SWI/SNF
Subject categories Cancer and Oncology

Abstract

Myxoid liposarcoma (MLS) shows extensive intratumoural heterogeneity with distinct subpopulations of tumour cells. Despite improved survival of MLS patients, existing therapies have shortcomings as they fail to target all tumour cells. The nature of chemotherapy-resistant cells in MLS remains unknown. Here, we show that MLS cell lines contained subpopulations of cells that can form spheres, efflux Hoechst dye and resist doxorubicin, all properties attributed to cancer stem cells (CSCs). By single-cell gene expression, western blot, phospho-kinase array, immunoprecipitation, immunohistochemistry, flow cytometry and microarray analysis we showed that a subset of MLS cells expressed JAK–STAT genes with active signalling. JAK1/2 inhibition via ruxolitinib decreased, while stimulation with LIF increased, phosphorylation of STAT3 and the number of cells with CSC properties indicating that JAK–STAT signalling controlled the number of cells with CSC features. We also show that phosphorylated STAT3 interacted with the SWI/SNF complex. We conclude that MLS contains JAK–STAT-regulated subpopulations of cells with CSC features. Combined doxorubicin and ruxolitinib treatment targeted both proliferating cells as well as cells with CSC features, providing new means to circumvent chemotherapy resistance in treatment of MLS patients. © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

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