{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:07:31Z","timestamp":1792714051955,"version":"4.5.0"},"reference-count":79,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    GPNMB (glycoprotein nonmetastatic B) and other TFE3\/TFEB transcriptional targets have been proposed as markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs). We recently demonstrated that constitutive mTORC1 activation via\n                    <jats:italic>TSC1\/2<\/jats:italic>\n                    loss leads to increased activity of TFE3\/TFEB, suggesting that the pathogenesis and molecular markers for tRCCs and TSC1\/2\u2010associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with\n                    <jats:italic>TSC2<\/jats:italic>\n                    and\/or\n                    <jats:italic>TFE3\/TFEB<\/jats:italic>\n                    loss produced using CRISPR\u2013Cas9 genome editing as well as in a mouse model of\n                    <jats:italic>Tsc2<\/jats:italic>\n                    inactivation\u2010driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200987), papillary RCC (papRCC,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200953), chromophobe RCC (chRCC,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200934), oncocytoma (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094),\n                    <jats:italic>TFE3<\/jats:italic>\n                    \u2010 or\n                    <jats:italic>TFEB<\/jats:italic>\n                    \u2010driven tRCC (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200956), eosinophilic solid and cystic RCC (ESC,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20096), eosinophilic vacuolated tumor (EVT,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20094), and low\u2010grade oncocytic tumor (LOT,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093), as well as AML (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200929) and perivascular epithelioid cell tumors (PEComas,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098). In cell lines, GPNMB was upregulated following\n                    <jats:italic>TSC2<\/jats:italic>\n                    loss in a MiT\/TFE\u2010 and mTORC1\u2010dependent fashion. Renal tumors in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    A\/J mice showed upregulation of GPNMB compared with normal kidney. Mean GPNMB expression was significantly higher in tRCC than in ccRCC (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001), papRCC (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001), and chRCC (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001). GPNMB expression in\n                    <jats:italic>TSC1\/2\/MTOR<\/jats:italic>\n                    alteration\u2010associated renal tumors (including ESC, LOT, AML, and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and\n                    <jats:italic>TSC1\/2\/MTOR<\/jats:italic>\n                    alteration\u2010associated renal tumors is highly overlapping, likely due to the increased activity of TFE3\/TFEB in both, revealing an important caveat regarding the use of TFE3\/TFEB\u2010transcriptional targets as diagnostic markers. \u00a9 2022 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.5875","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T11:55:40Z","timestamp":1643025340000},"page":"158-171","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":123,"title":["<scp>GPNMB<\/scp>\n                    expression identifies\n                    <scp>TSC1<\/scp>\n                    \/2\/\n                    <scp>mTOR<\/scp>\n                    \u2010associated and\n                    <scp>MiT<\/scp>\n                    family translocation\u2010driven renal neoplasms"],"prefix":"10.1002","volume":"257","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1904-185X","authenticated-orcid":false,"given":"Daniela C","family":"Salles","sequence":"first","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaushal","family":"Asrani","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juhyung","family":"Woo","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"Vidotto","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans B","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Matoso","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George J","family":"Netto","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Alabama  Birmingham AL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedram","family":"Argani","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0494-9067","authenticated-orcid":false,"given":"Tamara L","family":"Lotan","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University School of Medicine  Baltimore MD USA"},{"name":"Department of Urology Johns Hopkins University School of Medicine  Baltimore MD USA"},{"name":"Department of Oncology Johns Hopkins University School of Medicine  Baltimore MD 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