Exploring anti-stem cell therapy in colorectal cancer

▸ Storm EE, Durinck S, de Sousa e Melo F, et al. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem cell function. Nature 2016;529:97–100.

Adenomatous polyposis coli mutations resulting in activation of the WNT pathway are thought to be a founder event in the majority of human colorectal cancers (CRCs), yet targeting the WNT pathway has not yielded any effective therapies. There is a subset of CRCs that express recurrent gene fusions of members of the R-spondin (RSPO, WNT agonists) that exhibit WNT activation through translocation, without WNT pathway mutations. Antibodies to RSPO2 and RSPO3, and patient cancers with this phenotype that produce murine xenografts have been identified. Administering anti-RSPO3 to mice with xenografts stopped tumour growth, although it did not reduce the overall tumour size. To determine the underlying mechanisms, the authors performed RNA seq on anti-RSPO3-treated xenografts and demonstrated that the overall WNT target genes were downregulated (as would have been predicted). Upon closer examination, there was a significant downregulation of stem cell–associated mRNA (LGR5, ASCL2) and upregulation of genes that promote or are markers of cellular differentiation (TFF1 and KRT20). Therefore, treated fusion tumours exhibited more differentiated phenotype than non-treated fusion tumours. To determine the effects of anti-RSPO3 on normal intestinal stem cell homeostasis and regeneration, the antibody was injected into normal mice and those that had been exposed to irradiation. While the stem cell population appeared to be ablated with anti-RSPO3 (the effect amplified when co-injected with anti-RSPO2), there were no obvious histological effects on the intestine. However, postirradiation, anti-RSPO3 severely impaired the ability of the normal intestine to recover (and this effect was amplified by combining this with anti-RSPO2). This demonstrates a critical role for RSPO3 in tissue regeneration. Finally, anti-RSPO3 depletion of xenograft murine stem cells impacted on tumour growth. In a xenograft …