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Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
Paola Zordan, … , Pietro L. Poliani, Rossella Galli
Paola Zordan, … , Pietro L. Poliani, Rossella Galli
Published February 1, 2018
Citation Information: J Clin Invest. 2018;128(4):1688-1706. https://doi.org/10.1172/JCI96342.
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Research Article Neuroscience Article has an altmetric score of 9

Tuberous sclerosis complex–associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt

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Abstract

Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.

Authors

Paola Zordan, Manuela Cominelli, Federica Cascino, Elisa Tratta, Pietro L. Poliani, Rossella Galli

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Figure 10

SEGA pNSCs are endowed with tumorigenic potential and give rise to secondary tumors that resemble the corresponding human lesions both histologically and molecularly.

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SEGA pNSCs are endowed with tumorigenic potential and give rise to secon...
(A) Tumors generated by the s.c. implantation of distinct pNSCs (H&E, right) reproduced the heterogeneity in morphology and cell composition observed in human SEGA samples (H&E, left). pNSC line L3–derived tumors were characterized by the prevalence of spindle-shaped cells, as in human specimen 3. Conversely, mouse SEGAs from L90 contained mostly large and giant cells, some of which were also multinucleated (arrows), as retrieved in patients 5 and 6. Tumors from line L1 comprised both spindle-shaped and giant cells at similar frequency, as shown in patients 10 and 13. (Original magnification, ×400 and ×600 in human samples; in mouse samples: L3 and L90 tumors, ×200, ×400, and ×600; L1 tumors, ×400 and ×600). (B) Subcutaneous tumors activated pS6, pAktS473, pErk, and pNDRG1 (×600). Representative P15–17 TPN pNSC line L3. (C) Heatmap showing the top 10 increased/decreased genes differentially expressed between control pNSCs and mouse SEGAs, ranked based on their P value (P < 0.001). Blue, low; red, high (n = 3 independent biological replicates for each condition). Quantitative PCR analysis confirms Gpnmb as the top-ranking upregulated gene in mouse SEGAs (n = 3 independent biological replicates for each condition). Quantitative PCR results are expressed as the mean ± SEM. Two-group comparisons were performed with the independent-samples t test. *P < 0.05 (P = 0.0216). (D) GSEA enrichment plot indicating that the 809 genes upregulated in human SEGAs versus normal control human brain tissue positively correlated with genes preranked based on their expression in pNSC-derived mouse SEGAs versus control pNSCs. Nominal P < 0.00001; FDR q < 0.00001; enrichment score, 0.178; normalized enrichment score, 5.69.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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