bims-tubesc 2022-09-18 papers

Issue of 2022–09–18
eight papers selected by

Orphanet J Rare Dis. 2022 Sep 14. 17(1): 355

Characterization and management of facial angiofibroma related to tuberous sclerosis complex in the United States: retrospective analysis of the natural history database.

Sreedevi Boggarapu, Steven L Roberds, JoAnne Nakagawa, Eric Beresford.

BACKGROUND: Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance's Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006.
RESULTS: Of the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11-17 (odds ratio [OR], 2.53) and 18-45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11-17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33).
CONCLUSIONS: The presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.

Keywords: Facial angiofibroma; Mechanistic target of rapamycin; Surgical removal; Topical mTOR inhibitor; Tuberous sclerosis complex

DOI: https://doi.org/10.1186/s13023-022-02496-2

Front Med (Lausanne). 2022 ;9 967971

Impact of facial angiofibromas in tuberous sclerosis complex and reported efficacy of available treatments.

Marie Monaghan, Pooja Takhar, Luke Langlands, Markus Knuf, Sam Amin.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

Keywords: TSC; facial angiofibromas; rapamycin; sirolimus; tuberous sclerosis

DOI: https://doi.org/10.3389/fmed.2022.967971

Int J Oncol. 2022 Nov;pii: 132. [Epub ahead of print]61(5):

A multi‑omics study of diagnostic markers and the unique inflammatory tumor micro‑environment involved in tuberous sclerosis complex‑related renal angiomyolipoma.

Zhan Wang, Xiaoyan Liu, Wenda Wang, Jing Wei, Samuel Seery, Jiyu Xu, Haidan Sun, Yuncui Yu, Yang Zhao, Xu Wang, Zhangcheng Liao, Yanan Li, Wei Sun, Lulu Jia, Yushi Zhang.

Tuberous sclerosis complex (TSC) is a rare disease that threatens multiple organs in the human body. TSC‑associated renal angiomyolipoma (TSC‑RAML) has potentially life‑threatening complications and a generally poor prognosis. The present study aimed to find plasma proteomic diagnostics and disease‑associated markers, and explore the tumor microenvironment using multi‑omics. To achieve this goal, the plasma proteomics as well as tissue proteomics, bulk and single‑cell RNA transcriptome from patients with TSC‑RAML were examined and analyzed. The results suggested that plasma proteins such as MMP9 and C‑C motif chemokine ligand 5 were able to differentiate TSC‑RAML from sporadic angiomyolipoma and renal cyst. A correlation analysis revealed that plasma proteomics were associated with lymphangioleiomyomatosis, TSC‑RAML grading and whole‑body disease burden. Tissue proteomics of participants with TSC‑RAML revealed disturbed small molecule catabolic process, mitochondrial matrix component and actin binding function. Bulk and single‑cell RNA sequencing suggested a greater number of tumor‑like cells, fibroblasts and mononuclear macrophages within the tumor microenvironment. The above results indicated that TSC‑RAML exhibited a characteristic and disease‑associated plasma proteomic profile. The unique microenvironment, made up of fibroblasts and mono‑macrophages, may promote tumorigenesis and TSC‑RAML progression.

Keywords: RNA transcriptome; UPLC‑MS; diagnostic markers; proteomics; tuberous sclerosis complex; tumor microenvironment

DOI: https://doi.org/10.3892/ijo.2022.5422

PLoS Biol. 2022 Sep;20(9): e3001737

Cytoskeletal vimentin regulates cell size and autophagy through mTORC1 signaling.

Ponnuswamy Mohanasundaram, Leila S Coelho-Rato, Mayank Kumar Modi, Marta Urbanska, Franziska Lautenschläger, Fang Cheng, John E Eriksson.

The nutrient-activated mTORC1 (mechanistic target of rapamycin kinase complex 1) signaling pathway determines cell size by controlling mRNA translation, ribosome biogenesis, protein synthesis, and autophagy. Here, we show that vimentin, a cytoskeletal intermediate filament protein that we have known to be important for wound healing and cancer progression, determines cell size through mTORC1 signaling, an effect that is also manifested at the organism level in mice. This vimentin-mediated regulation is manifested at all levels of mTOR downstream target activation and protein synthesis. We found that vimentin maintains normal cell size by supporting mTORC1 translocation and activation by regulating the activity of amino acid sensing Rag GTPase. We also show that vimentin inhibits the autophagic flux in the absence of growth factors and/or critical nutrients, demonstrating growth factor-independent inhibition of autophagy at the level of mTORC1. Our findings establish that vimentin couples cell size and autophagy through modulating Rag GTPase activity of the mTORC1 signaling pathway.

DOI: https://doi.org/10.1371/journal.pbio.3001737

Sci Adv. 2022 Sep 16. 8(37): eadd2926

Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation.

Rachel M Jansen, Roberta Peruzzo, Simon A Fromm, Adam L Yokom, Roberto Zoncu, James H Hurley.

The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell growth and catabolism in response to nutrients through phosphorylation of key substrates. The tumor suppressor folliculin (FLCN) is a RagC/D guanosine triphosphatase (GTPase)-activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE transcription factors, controlling lysosome biogenesis and autophagy. We determined the cryo-electron microscopy structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagAGDP:RagCGDP.BeFx- GTPase dimer, and the Ragulator scaffold. Relative to the inactive lysosomal FLCN complex structure, FLCN reorients by 90°, breaks contact with RagA, and makes previously unseen contacts with RagC that position its Arg164 finger for catalysis. Disruption of the AFC-specific interfaces of FLCN and FNIP2 with RagC eliminated GAP activity and led to nuclear retention of TFE3, with no effect on mTORC1 substrates S6K or 4E-BP1. The structure provides a basis for regulation of an mTORC1 substrate-specific pathway and a roadmap to discover MiT-TFE family selective mTORC1 antagonists.

DOI: https://doi.org/10.1126/sciadv.add2926

Nat Cell Biol. 2022 Sep;24(9): 1394-1406

A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids.

Peter Gollwitzer, Nina Grützmacher, Sabine Wilhelm, Daniel Kümmel, Constantinos Demetriades.

Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and effectors. Mammalian cells express four Rag proteins (RagA-D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies. Here, by using genetically modified cell lines that express single Rag heterodimers, we uncover a Rag dimer code that determines how amino acids regulate mTORC1. First, RagC/D differentially define the substrate specificity downstream of mTORC1, with RagD promoting phosphorylation of its lysosomal substrates TFEB/TFE3, while both Rags are involved in the phosphorylation of non-lysosomal substrates such as S6K. Mechanistically, RagD recruits mTORC1 more potently to lysosomes through increased affinity to the anchoring LAMTOR complex. Furthermore, RagA/B specify the signalling response to amino acid removal, with RagB-expressing cells maintaining lysosomal and active mTORC1 even upon starvation. Overall, our findings reveal key qualitative differences between Rag paralogues in the regulation of mTORC1, and underscore Rag gene duplication and diversification as a potentially impactful event in mammalian evolution.

DOI: https://doi.org/10.1038/s41556-022-00976-y

Nat Cell Biol. 2022 Sep;24(9): 1407-1421

Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition.

Gianluca Figlia, Sandra Müller, Anna M Hagenston, Susanne Kleber, Mykola Roiuk, Jan-Philipp Quast, Nora Ten Bosch, Damian Carvajal Ibañez, Daniela Mauceri, Ana Martin-Villalba, Aurelio A Teleman.

Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to appropriately regulate cellular anabolism and catabolism. During nutrient restriction, different organs in an animal do not respond equally, with vital organs being relatively spared. This raises the possibility that mTORC1 is differentially regulated in different cell types, yet little is known about this mechanistically. The Rag GTPases, RagA or RagB bound to RagC or RagD, tether mTORC1 in a nutrient-dependent manner to lysosomes where mTORC1 becomes activated. Although the RagA and B paralogues were assumed to be functionally equivalent, we find here that the RagB isoforms, which are highly expressed in neurons, impart mTORC1 with resistance to nutrient starvation by inhibiting the RagA/B GTPase-activating protein GATOR1. We further show that high expression of RagB isoforms is observed in some tumours, revealing an alternative strategy by which cancer cells can retain elevated mTORC1 upon low nutrient availability.

DOI: https://doi.org/10.1038/s41556-022-00977-x