Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling
Program in Molecular Medicine
Cancer Biology | Neoplasms | Oncology | Translational Medical Research
The effects of polarized membrane trafficking in mature epithelial tissue on cell growth and cancer progression have not been fully explored in vivo. A majority of colorectal cancers have reduced and mislocalized Rab11, a small GTPase dedicated to trafficking of recycling endosomes. Patients with low Rab11 protein expression have poor survival rates. Using genetic models across species, we show that intact recycling endosome function restrains aberrant epithelial growth elicited by APC or RAS mutations. Loss of Rab11 protein led to epithelial dysplasia in early animal development and synergized with oncogenic pathways to accelerate tumor progression initiated by carcinogen, genetic mutation, or aging. Transcriptomic analysis uncovered an immediate expansion of the intestinal stem cell pool along with cell-autonomous Yki/Yap activation following disruption of Rab11a-mediated recycling endosomes. Intestinal tumors lacking Rab11a traffic exhibited marked elevation of nuclear Yap, upd3/IL6-Stat3, and amphiregulin-MAPK signaling, whereas suppression of Yki/Yap or upd3/IL6 reduced gut epithelial dysplasia and hyperplasia. Examination of Rab11a function in enteroids or cultured cell lines suggested that this endosome unit is required for suppression of the Yap pathway by Hippo kinases. Thus, recycling endosomes in mature epithelia constitute key tumor suppressors, loss of which accelerates carcinogenesis.
SIGNIFICANCE: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism.
DOI of Published Version
D'Agostino L, Nie Y, Goswami S, Tong K, Yu S, Bandyopadhyay S, Flores J, Zhang X, Balasubramanian I, Joseph I, Sakamori R, Farrell V, Li Q, Yang CS, Gao B, Ferraris RP, Yehia G, Bonder EM, Goldenring JR, Verzi MP, Zhang L, Ip YT, Gao N. Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling. Cancer Res. 2019 Aug 15;79(16):4099-4112. doi: 10.1158/0008-5472.CAN-18-4075. Epub 2019 Jun 25. PMID: 31239271; PMCID: PMC6726494. Link to article on publisher's site
D'Agostino L, Nie Y, Li Q, Ip YT, Gao N. (2019). Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling. UMass Center for Clinical and Translational Science Supported Publications. https://doi.org/10.1158/0008-5472.CAN-18-4075. Retrieved from https://escholarship.umassmed.edu/umccts_pubs/204