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    Recycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling

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    Authors
    D'Agostino, Luca
    Nie, Yingchao
    Li, Qi
    Ip, Y. Tony
    Gao, Nan
    UMass Chan Affiliations
    Program in Molecular Medicine
    Document Type
    Journal Article
    Publication Date
    2019-08-15
    Keywords
    UMCCTS funding
    Cancer Biology
    Neoplasms
    Oncology
    Translational Medical Research
    
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726494/
    Abstract
    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.
    Source

    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

    DOI
    10.1158/0008-5472.CAN-18-4075
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/50377
    PubMed ID
    31239271
    Notes

    Full author list omitted for brevity. For the full list of authors, see article.

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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1158/0008-5472.CAN-18-4075
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