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Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway

Haruna Kawano1, Yoshitaka Ito2, Fumio Kanai3

  • 1Department of Urology, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan.

Oncology Reports
|September 10, 2015
PubMed

Insights

Tsc2 gene mutations in Eker rats cause renal cell carcinoma. Researchers created Tsc2-deficient stem cells to model these tumors, revealing mTORC1 pathway activation and TFE3 nuclear localization, key factors in tumor development.

Area of Science:

  • Oncology
  • Developmental Biology
  • Genetics

Background:

  • The Eker rat, a model for renal cell carcinoma (RCC), harbors a germline mutation in the tuberous sclerosis 2 (Tsc2) gene.
  • Heterozygous mutants develop RCCs via a second hit, while homozygous mutants are embryonically lethal.

Purpose of the Study:

  • To develop a novel cell differentiation model for studying Tsc2 mutation-associated pathogenesis.
  • To investigate the mechanisms underlying tumorigenesis in Tsc2-deficient models.

Main Methods:

  • Generation of Tsc2-deficient embryonic stem cells (ESCs) from Eker rats (Tsc2+/+, Tsc2+/-, Tsc2-/-).
  • Teratoma formation assays using ESCs.
  • Immunohistochemical analysis of teratomas and Eker rat RCCs for mTORC1 signaling markers (p-S6, p-4EBP1), epithelial markers (megalin, cubilin), E-cadherin, β-catenin, and TFE3.

Main Results:

  • Tsc2-/- ESCs formed teratomas with abnormal epithelial tumor-like ductal structures.
  • Activated mammalian target of rapamycin complex 1 (mTORC1) signaling was observed in these abnormal ducts.
  • Nuclear localization of the mTORC1-regulated transcription factor TFE3 was found in abnormal ducts and Eker rat RCCs, similar to epithelial marker expression and cell adhesion molecule localization.

Conclusions:

  • Tsc2-deficient ESCs provide a new experimental tool for analyzing differentiation defects and pathogenesis associated with Tsc2 deficiency.
  • TFE3, as a negative regulator of ESC differentiation, may contribute to tissue-specific differentiation defects and tumorigenesis in Tsc2-deficient models.
  • The study highlights the role of mTORC1 signaling and TFE3 in the development of RCC in the Eker rat model.

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