Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function

Antibody-mediated inhibition of R-spondin-3 in colorectal tumours decreases tumour growth and promotes differentiation—these effects are associated with a decrease in expression of genes associated with stem-cell function. Stem cell function in colorectal tumours Frederic de Sauvage and colleagues have previously identified translocations in genes encoding the Wnt regulator R-spondins in some colorectal tumours. Here they demonstrate that antibody-mediated inhibition of R-spondin 3 (RSPO3) in such tumours decreases tumour growth and promotes differentiation. These effects are associated with a decrease in expression of genes associated with stem cell function. This work raises the possibility of targeting stem -cell properties within tumours as therapeutic approach in colorectal tumours. Colorectal cancer remains a major unmet medical need, prompting large-scale genomics efforts in the field to identify molecular drivers for which targeted therapies might be developed 1 , 2 , 3 . We previously reported the identification of recurrent translocations in R-spondin genes present in a subset of colorectal tumours 4 . Here we show that targeting RSPO3 in PTPRK-RSPO3 -fusion-positive human tumour xenografts inhibits tumour growth and promotes differentiation. Notably, genes expressed in the stem-cell compartment of the intestine were among those most sensitive to anti-RSPO3 treatment. This observation, combined with functional assays, suggests that a stem-cell compartment drives PTPRK-RSPO3 colorectal tumour growth and indicates that the therapeutic targeting of stem-cell properties within tumours may be a clinically relevant approach for the treatment of colorectal tumours.