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Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer

2018; Nature Portfolio; Volume: 20; Issue: 10 Linguagem: Inglês

10.1038/s41556-018-0179-z

1476-4679

Kristiaan Lenos, Daniël M. Miedema, Sophie C. Lodestijn, Lisanne E. Nijman, Tom van den Bosch, Xavier Romero Ros, Filipe C. Lourenço, Maria C. Lecca, Maartje van der Heijden, Sanne M. van Neerven, Anita van Oort, Nicolas Léveillé, R. Adam, Felipe de Sousa e Melo, Joy Otten, Patrick Veerman, Guillaume Hypolite, Lianne Koens, Scott K. Lyons, Giorgio Stassi, Douglas J. Winton, Jan Paul Medema, Edward Morrissey, Maarten F. Bijlsma, Louis Vermeulen,

Cancer Genomics and Diagnostics

Solid malignancies have been speculated to depend on cancer stem cells (CSCs) for expansion and relapse after therapy. Here we report on quantitative analyses of lineage tracing data from primary colon cancer xenograft tissue to assess CSC functionality in a human solid malignancy. The temporally obtained clone size distribution data support a model in which stem cell function in established cancers is not intrinsically, but is entirely spatiotemporally orchestrated. Functional stem cells that drive tumour expansion predominantly reside at the tumour edge, close to cancer-associated fibroblasts. Hence, stem cell properties change in time depending on the cell location. Furthermore, although chemotherapy enriches for cells with a CSC phenotype, in this context functional stem cell properties are also fully defined by the microenvironment. To conclude, we identified osteopontin as a key cancer-associated fibroblast-produced factor that drives in situ clonogenicity in colon cancer. Lenos et al. report that the spatiotemporal regulation of stem cell functionality is not intrinsically determined but environmentally defined during tumour growth and drug response in colon cancer.