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

• DOI: 10.1038/s41556-018-0179-z
• Publication Date: 2018-08-24T16:13:02Z
• Authors: Kristiaan J. 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 H...; Sanne M. van Neerven; Anita van Oort; Nicolas Leveille; Ronja S. Adam; Felipe de Sousa E...; 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
• Keywords: 0303 health sciences; Gene Expression Profiling; 610; Mice, Nude; Colon cancer, cancer stem cells, tumor microenvironment.; Xenograft Model Antitumor Assays; Article; 3. Good health; Gene Expression Regulation, Neoplastic; Oxaliplatin; Tamoxifen; 03 medical and health sciences; colon cancer; stem cells; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment; Animals; Humans; Cells, Cultured; Cell Proliferation

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.