Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 145, Issue 2, Pages 435-449Publisher
WILEY
DOI: 10.1002/ijc.32123
Keywords
cancer stem cells; chemotherapy resistance; JAK-STAT signalling; LIF; myxoid liposarcoma; ruxolitinib; SWI; SNF
Categories
Funding
- Barncancerfonden [2017-0043]
- Cancerfonden [2015-7130, 2016-438]
- Stiftelsen Assar Gabrielssons Fond
- Svenska Sallskapet for Medicinsk Forskning
- Vetenskapsradet [2017-01392]
- Wilhelm and Martina Lundgren Foundation for Scientific Research
- VINNOVA
- Swedish state [722211, 716321]
- Knut and Alice Wallenberg Foundation
- Wallenberg Centre for molecular and translational medicine at University of Gothenburg, Sweden
- Johan Jansson Foundation for Cancer Research
- BioCARE National Strategic Research Program at University of Gothenburg
- Formas [2017-01392] Funding Source: Formas
- Swedish Research Council [2017-01392] Funding Source: Swedish Research Council
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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.
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