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dc.contributor.authorD'Agostino, Luca
dc.contributor.authorNie, Yingchao
dc.contributor.authorLi, Qi
dc.contributor.authorIp, Y. Tony
dc.contributor.authorGao, Nan
dc.date2022-08-11T08:11:02.000
dc.date.accessioned2022-08-23T17:29:42Z
dc.date.available2022-08-23T17:29:42Z
dc.date.issued2019-08-15
dc.date.submitted2019-09-18
dc.identifier.citation<p>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. <a href="https://doi.org/10.1158/0008-5472.CAN-18-4075">Link to article on publisher's site</a></p>
dc.identifier.issn0008-5472 (Linking)
dc.identifier.doi10.1158/0008-5472.CAN-18-4075
dc.identifier.pmid31239271
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50377
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractThe 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31239271&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726494/
dc.subjectUMCCTS funding
dc.subjectCancer Biology
dc.subjectNeoplasms
dc.subjectOncology
dc.subjectTranslational Medical Research
dc.titleRecycling Endosomes in Mature Epithelia Restrain Tumorigenic Signaling
dc.typeJournal Article
dc.source.journaltitleCancer research
dc.source.volume79
dc.source.issue16
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/umccts_pubs/204
dc.identifier.contextkey15360841
html.description.abstract<p>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.</p> <p>SIGNIFICANCE: Recycling endosome traffic in mature epithelia constitutes a novel tumor suppressing mechanism.</p>
dc.identifier.submissionpathumccts_pubs/204
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages4099-4112


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