Activating translocations of RSPO2 and RSPO3 that are mutually exclusive with other Wnt-activating mutations have been shown to drive the development of colon cancer [13–14], and we recently demonstrated through a forward genetics approach that Rspo2 is a major determinant of susceptibility to C. rodentium-mediated infectious colitis in mice [15]. Here, RSPO2 is linked to malignant colon neoplasm.