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GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms

Daniela C Salles1, Kaushal Asrani1, Juhyung Woo1

  • 1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The Journal of Pathology
|January 24, 2022
PubMed

Insights

Glycoprotein nonmetastatic B (GPNMB) is upregulated in TFE3/TFEB-driven tumors and TSC1/2-associated renal tumors. This overlap challenges GPNMB

Area of Science:

  • Nephrology
  • Oncology
  • Molecular Biology

Background:

  • Glycoprotein nonmetastatic B (GPNMB) and TFE3/TFEB targets are potential markers for microphthalmia (MiT) translocation renal cell carcinomas (tRCCs).
  • Constitutive mTORC1 activation via TSC1/2 loss increases TFE3/TFEB activity, suggesting overlapping pathogenesis and markers between tRCCs and TSC1/2-associated tumors.

Purpose of the Study:

  • To investigate GPNMB expression in various human and mouse kidney tumor models with TSC2 and/or TFE3/TFEB alterations.
  • To assess the diagnostic utility of GPNMB as a marker for tRCCs and related tumors.

Main Methods:

  • CRISPR-Cas9 genome editing was used to create kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss.
  • An automated immunohistochemistry (IHC) assay and digital image analysis quantified GPNMB expression in diverse renal tumor subtypes and AMLs.
  • GPNMB expression was analyzed in a mouse model of Tsc2 inactivation-driven renal tumorigenesis.

Main Results:

  • GPNMB was upregulated in cell lines with TSC2 loss, dependent on MiT/TFE and mTORC1.
  • Renal tumors in Tsc2+/- mice showed increased GPNMB expression compared to normal kidney.
  • Mean GPNMB expression was significantly higher in tRCCs than in clear cell, papillary, and chromophobe RCCs.
  • GPNMB expression in TSC1/2/mTOR-altered tumors (including AMLs) was comparable to tRCCs.

Conclusions:

  • The immunophenotype of tRCCs and TSC1/2/mTOR-altered renal tumors significantly overlaps.
  • This overlap is likely due to increased TFE3/TFEB activity in both tumor types.
  • The findings reveal a critical caveat regarding the use of TFE3/TFEB transcriptional targets as standalone diagnostic markers for tRCCs.
Keywords:
GPNMBTFE3TFEBTSC1/2angiomyolipomarenal cell carcinomatranslocation renal cell carcinoma

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