Aberrant Differentiation of Tsc2-deficient Teratomas Associated with Activation of the MTORC1-TFE3 Pathway

Overview

Journal Oncol Rep

Specialty Oncology

Date 2015 Sep 10

PMID 26352760

Citations 7

Authors

Haruna Kawano

Yoshitaka Ito

Fumio Kanai

Eri Nakamura

Norihiro Tada

Setsuo Takai

Shigeo Horie

Toshiyuki Kobayashi

Okio Hino

Affiliations

Soon will be listed here.

Abstract

The model animal of renal cell carcinoma (RCC), the Eker rat, has a germline mutation in the tuberous sclerosis 2 (Tsc2) gene. Heterozygous mutants develop RCCs by second hit in the wild-type Tsc2 allele, whereas homozygous mutants are embryonic lethal. In the present study, a new cell differentiation model was developed to study the mechanism of Tsc2 mutation-associated pathogenesis by generating Tsc2-deficient embryonic stem cells (ESCs) from Eker rats. Tsc2+/+, Tsc2+/- and Tsc2-/- ESCs were all capable of generating three germ layers: mesoderm, ectoderm, and endoderm. Interestingly, epithelial tumor-like abnormal ductal structures were reproducibly observed in Tsc2-/- teratomas from different ESC lines. Immunohistochemical analysis revealed that mammalian target of rapamycin complex 1 (mTORC1) signaling was activated in abnormal ducts of Tsc2-/- teratomas, on the basis of positive staining for p-S6 and p-4EBP1. In these abnormal ducts, expression levels of epithelial markers (i.e., megalin and cubilin) and the cytoplasmic localization of E-cadherin and β-catenin were similar to those in Eker rat RCCs. Moreover, a transcription factor regulated by mTORC1, named TFE3, was located in the nuclei of abnormal ducts and Eker rat RCCs. As a negative regulator of ESC differentiation, TFE3 may result in tissue-specific differentiation defects related to tumorigenesis in Eker rats and Tsc2-/- teratomas. The present study suggests that ESCs derived from Eker rats constitute a novel experimental tool with which to analyze differentiation defects and cell-type specific pathogenesis associated with Tsc2 deficiency.

Citing Articles

Renal epithelioid angiomyolipomas overexpress TFE3 and the TFE3-regulated gene TRIM63 in the absence of TFE3 rearrangement.

Collins K, Bridge J, Mehra R, Mannan R, Dickson B, Lotan T Virchows Arch. 2024; 485(3):471-478.

PMID: 38971946 DOI: 10.1007/s00428-024-03855-z.

An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss.

Asrani K, Woo J, Mendes A, Schaffer E, Vidotto T, Villanueva C Nat Commun. 2022; 13(1):6808.

PMID: 36357396 PMC: 9649702. DOI: 10.1038/s41467-022-34617-7.

Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the Alzheimer's Disease Model.

Shi Q, Chang C, Saliba A, Bhat M J Neurosci. 2022; 42(27):5294-5313.

PMID: 35672148 PMC: 9270922. DOI: 10.1523/JNEUROSCI.2427-21.2022.

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

Salles D, Asrani K, Woo J, Vidotto T, Liu H, Vidal I J Pathol. 2022; 257(2):158-171.

PMID: 35072947 PMC: 9310781. DOI: 10.1002/path.5875.

A novel TSC1 variant associated with tuberous sclerosis and sacrococcygeal teratoma.

Ahmad S, Manon L, Bhat G, Machado J, Zalan A, Mata-Machado N Hum Genome Var. 2020; 7(1):39.

PMID: 33298910 PMC: 7677537. DOI: 10.1038/s41439-020-00124-8.

References

McDorman K, Wolf D . Use of the spontaneous Tsc2 knockout (Eker) rat model of hereditary renal cell carcinoma for the study of renal carcinogens. Toxicol Pathol. 2003; 30(6):675-80. DOI: 10.1080/01926230290168542. View

Kielman M, Rindapaa M, Gaspar C, van Poppel N, Breukel C, van Leeuwen S . Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling. Nat Genet. 2002; 32(4):594-605. DOI: 10.1038/ng1045. View

Sarbassov D, Ali S, Kim D, Guertin D, Latek R, Erdjument-Bromage H . Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004; 14(14):1296-302. DOI: 10.1016/j.cub.2004.06.054. View

Knudson Jr A . Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971; 68(4):820-3. PMC: 389051. DOI: 10.1073/pnas.68.4.820. View

Takeichi M . Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 1991; 251(5000):1451-5. DOI: 10.1126/science.2006419. View

Everitt J, Goldsworthy T, Wolf D, Walker C . Hereditary renal cell carcinoma in the Eker rat: a rodent familial cancer syndrome. J Urol. 1992; 148(6):1932-6. DOI: 10.1016/s0022-5347(17)37087-8. View

Hino O, Klein-Szanto A, FREED J, Testa J, Brown D, Vilensky M . Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci U S A. 1993; 90(1):327-31. PMC: 45653. DOI: 10.1073/pnas.90.1.327. View

Kandt R, Haines J, Smith M, Northrup H, Gardner R, Short M . Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet. 1992; 2(1):37-41. DOI: 10.1038/ng0992-37. View

. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993; 75(7):1305-15. DOI: 10.1016/0092-8674(93)90618-z. View

10.

Larue L, Ohsugi M, Hirchenhain J, Kemler R . E-cadherin null mutant embryos fail to form a trophectoderm epithelium. Proc Natl Acad Sci U S A. 1994; 91(17):8263-7. PMC: 44586. DOI: 10.1073/pnas.91.17.8263. View

11.

Yeung R, Xiao G, Jin F, Lee W, Testa J, Knudson A . Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci U S A. 1994; 91(24):11413-6. PMC: 45241. DOI: 10.1073/pnas.91.24.11413. View

12.

Riethmacher D, Brinkmann V, Birchmeier C . A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. Proc Natl Acad Sci U S A. 1995; 92(3):855-9. PMC: 42719. DOI: 10.1073/pnas.92.3.855. View

13.

Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O . A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat Genet. 1995; 9(1):70-4. DOI: 10.1038/ng0195-70. View

14.

Wolf D, Whiteley H, Everitt J . Preneoplastic and neoplastic lesions of rat hereditary renal cell tumors express markers of proximal and distal nephron. Vet Pathol. 1995; 32(4):379-86. DOI: 10.1177/030098589503200406. View

15.

van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S . Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997; 277(5327):805-8. DOI: 10.1126/science.277.5327.805. View

16.

Cadigan K, Nusse R . Wnt signaling: a common theme in animal development. Genes Dev. 1998; 11(24):3286-305. DOI: 10.1101/gad.11.24.3286. View

17.

Rennebeck G, Kleymenova E, Anderson R, Yeung R, Artzt K, Walker C . Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci U S A. 1998; 95(26):15629-34. PMC: 28095. DOI: 10.1073/pnas.95.26.15629. View

18.

Roose J, Clevers H . TCF transcription factors: molecular switches in carcinogenesis. Biochim Biophys Acta. 1999; 1424(2-3):M23-37. DOI: 10.1016/s0304-419x(99)00026-8. View

19.

Huan C, Sashital D, Hailemariam T, Kelly M, Roman C . Renal carcinoma-associated transcription factors TFE3 and TFEB are leukemia inhibitory factor-responsive transcription activators of E-cadherin. J Biol Chem. 2005; 280(34):30225-35. DOI: 10.1074/jbc.M502380200. View

20.

VAN Roy F, Berx G . The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008; 65(23):3756-88. PMC: 11131785. DOI: 10.1007/s00018-008-8281-1. View