Recycling endosomes in mature epithelia restrain tumorigenic signaling

Abstract

The effects of polarized membrane trafficking in mature activation following disruption of Rab11a-mediated recy-epithelial tissue on cell growth and cancer progression have cling endosomes. Intestinal tumors lacking Rab11a traffic not been fully explored in vivo. A majority of colorectal cancers exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, have reduced and mislocalized Rab11, a small GTPase dedi- and amphiregulin-MAPK signaling, whereas suppression of cated to trafficking of recycling endosomes. Patients with low Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and Rab11 protein expression have poor survival rates. Using hyperplasia. Examination of Rab11a function in enteroids genetic models across species, we show that intact recycling or cultured cell lines suggested that this endosome unit is endosome function restrains aberrant epithelial growth eli-required for suppression of the Yap pathway by Hippo cited by APC or RAS mutations. Loss of Rab11 protein led to kinases. Thus, recycling endosomes in mature epithelia epithelial dysplasia in early animal development and syner-constitute key tumor suppressors, loss of which accelerates gized with oncogenic pathways to accelerate tumor progres-carcinogenesis. sion initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the Significance: Recycling endosome traffic in mature epithe-intestinal stem cell pool along with cell-autonomous Yki/Yap lia constitutes a novel tumor suppressing mechanism.