bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2022–01–30
eleven papers selected by
  1. Modeling tuberous sclerosis with organoids.
  2. Space-occupying Intraventricular Vascular Lesion in Tuberous Sclerosis Complex.
  3. Effectiveness of zonisamide in childhood refractory epilepsy.
  4. Long-term administration of sirolimus does not affect the physical development of children with tuberous sclerosis complex.
  5. Amplification of human interneuron progenitors promotes brain tumors and neurological defects.
  6. GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms.
  7. [Syndroms associated with benign skin tumors].
  8. TBC domain family 7-like enhances the tolerance of Penaeus vannamei to ammonia nitrogen by the up-regulation of autophagy.
  9. The mixed blessing of AMPK signaling in Cancer treatments.
  10. The impact of DAPK1 and mTORC1 signaling association on autophagy in cancer.
  11. Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2-Cre mice.
  1. Science. 2022 Jan 28. 375(6579): 382-383
    Modeling tuberous sclerosis with organoids.
    Rebecca A Ihrie, Elizabeth P Henske.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abn6158
  2. Neurologist. 2022 Jan 26.
    Space-occupying Intraventricular Vascular Lesion in Tuberous Sclerosis Complex.
    Hongtao Lv, Xiaotong Wang.
      
    DOI:  https://doi.org/10.1097/NRL.0000000000000415
  3. Childs Nerv Syst. 2022 Jan 27.
    Effectiveness of zonisamide in childhood refractory epilepsy.
    Mahmut Aslan, Serdal Gungor.
       INTRODUCTION: Zonisamide (ZNS) is a new generation antiepileptic drug (AED) used in refractory epilepsy. This study assessed the effectiveness and reliability of ZNS in childhood refractory epilepsy.
    METHOD: Sixty-eight epilepsy patients who were followed up in the paediatric neurology clinic, between 2013 and 2019, and in whom add-on therapy ZNS had been added as their seizures had continued despite multiple drugs being used, were included in this retrospective study. Their demographic findings, seizure aetiology, pre-treatment and post-treatment electroencephalography findings, treatment responses and any side effects of the drugs given were assessed in these patients.
    RESULTS: There were 46 (67.6%) patients in the refractory generalized epilepsy (RGE) group using multiple AEDs and 22 (32.35%) patients in the refractory focal epilepsy (RFE) group. Of these patients, 12 (17.65%) were being followed up for idiopathic epilepsy and 8 (11.76%) were being followed up for epilepsy of unknown aetiology. Twenty-two (32.36%) patients were followed up for structural abnormality, 8 patients (11.77%) were followed up for genetic disease, 4 patients (5.88%) were followed up for infectious sequel, 14 patients (20.59%) were followed up for metabolic reasons. In the RGE group, a more than 50% reduction was found in the seizures of 26 (56.5%) patients, while the seizures of 7 (15.2%) patients were found to have terminated completely. In the RFE group, a more than 50% reduction was found in the seizures of 19 (86.4%) patients, while the seizures of 2 (9.1%) patients were found to have terminated completely. The termination or a more than 50% reduction in seizures in 4 of the 6 patients followed up for a diagnosis of tuberous sclerosis complex (TSC) was significant.
    CONCLUSION: ZNS is an effective and reliable option as an add-on therapy in paediatric refractory epilepsy, especially in focal epilepsy. It can also be considered for treatment in TSC patients.
    Keywords:  Children; EEG; Refractory epilepsy; Zonisamide
    DOI:  https://doi.org/10.1007/s00381-022-05458-y
  4. Childs Nerv Syst. 2022 Jan 26.
    Long-term administration of sirolimus does not affect the physical development of children with tuberous sclerosis complex.
    Jian Chen, Wen He, Yang-Yang Wang, Meng-Na Zhang, Qian Lu, Qiu-Hong Wang, Xiao-Mei Luo, Bin Wang, Li-Ping Zou.
       PURPOSE: There was no evidence whether the mammalian/mechanistic target of rapamycin pathway hyperactivation and long-term use of mTOR inhibitors have any effects on the physical development of children. The aim was to evaluate these effects by comparing the physical development of children with TSC and normal children.
    METHODS: A total of 120 eligible children were enrolled. They were administered sirolimus and followed for at least 12 months. Height, weight, BMI and lipid metabolism index were collected during treatment. Pearson's chi-square and Fisher's exact test were used for comparison of proportions of patients exhibiting normal and abnormal physical growth before and after 1 year of treatment. Logistic regression was used to evaluate the influence of age, sex and abnormal lipid metabolism on the increased BMIs of TSC patients after treatment.
    RESULTS: Most of the enrolled TSC children were in the normal height, weight and BMI ranges at baseline (91.7%, 95.8% and 78.3%, respectively). Most remained in the normal height, weight and BMI ranges after 1 year of sirolimus treatment (94.2%, 95% and 76.7%, respectively). There was no significant difference in the proportion of physical development before and after treatment (p > 0.05). Thirty-eight (38/106, 35.8%) patients had increased BMIs after 1 year of treatment, but there was no significant correlation between age, sex and lipid metabolism and increased BMI.
    CONCLUSIONS: Overactivation of the mTOR pathway and long-term administration of sirolimus does not affect the physical development of children with TSC.
    Keywords:  Paediatric; Physical development; Sirolimus; Tuberous sclerosis
    DOI:  https://doi.org/10.1007/s00381-022-05446-2
  5. Science. 2022 Jan 28. 375(6579): eabf5546
    Amplification of human interneuron progenitors promotes brain tumors and neurological defects.
    Oliver L Eichmüller, Nina S Corsini, Ábel Vértesy, Ilaria Morassut, Theresa Scholl, Victoria-Elisabeth Gruber, Angela M Peer, Julia Chu, Maria Novatchkova, Johannes A Hainfellner, Mercedes F Paredes, Martha Feucht, Jürgen A Knoblich.
      Evolutionary development of the human brain is characterized by the expansion of various brain regions. Here, we show that developmental processes specific to humans are responsible for malformations of cortical development (MCDs), which result in developmental delay and epilepsy in children. We generated a human cerebral organoid model for tuberous sclerosis complex (TSC) and identified a specific neural stem cell type, caudal late interneuron progenitor (CLIP) cells. In TSC, CLIP cells over-proliferate, generating excessive interneurons, brain tumors, and cortical malformations. Epidermal growth factor receptor inhibition reduces tumor burden, identifying potential treatment options for TSC and related disorders. The identification of CLIP cells reveals the extended interneuron generation in the human brain as a vulnerability for disease. In addition, this work demonstrates that analyzing MCDs can reveal fundamental insights into human-specific aspects of brain development.
    DOI:  https://doi.org/10.1126/science.abf5546
  6. J Pathol. 2022 Jan 24.
    GPNMB expression identifies TSC1/2/mTOR-associated and MiT family translocation-driven renal neoplasms.
    Daniela C Salles, Kaushal Asrani, Juhyung Woo, Thiago Vidotto, Hans B Liu, Igor Vidal, Andres Matoso, George J Netto, Pedram Argani, Tamara L Lotan.
      GPNMB (Glycoprotein nonmetastatic B) and other TFE3/TFEB transcriptional targets have been proposed as markers for MiT translocation renal cell carcinomas (tRCC). We recently demonstrated that constitutive mTORC1 activation via TSC1/2 loss leads to increased activity of TFE3/TFEB, suggesting that the pathogenesis and molecular markers for tRCC and TSC1/2-associated tumors may be overlapping. We examined GPNMB expression in human kidney and angiomyolipoma (AML) cell lines with TSC2 and/or TFE3/TFEB loss produced using CRISPR-Cas9 genome editing as well as in a mouse model of Tsc2 inactivation-driven renal tumorigenesis. Using an automated immunohistochemistry (IHC) assay for GPNMB, digital image analysis was employed to quantitatively score expression in clear cell RCC (ccRCC, n=87), papillary RCC (papRCC, n=53), chromophobe RCC (chRCC, n=34), oncocytoma (n=4), TFE3- or TFEB-driven tRCC (n=56), eosinophilic solid and cystic RCC (ESC, n=6), eosinophilic vacuolated tumor (EVT, n=4) and low grade oncocytic tumor (LOT, n=3) as well as AML (n=29) and PEComa (n=8). In cell lines, GPNMB was up-regulated following TSC2 loss in a MiT/TFE- and mTORC1-dependent fashion. Renal tumors in Tsc2+/- A/J mice showed upregulation of GPNMB compared to normal kidney. Mean GPNMB expression was significantly higher in tRCC compared to ccRCC (p<0.0001), papRCC (p<0.0001) and chRCC (p<0.0001). GPNMB expression in TSC1/2/MTOR alteration-associated renal tumors (including ESC, LOT, AML and PEComa) was comparable to that in tRCC. The immunophenotype of tRCC and TSC1/2/MTOR alteration-associated renal tumors is highly overlapping, likely due to the increased activity of TFE3/TFEB in both, revealing an important caveat regarding the use of TFE3/TFEB-transcriptional targets as diagnostic markers. This article is protected by copyright. All rights reserved.
    Keywords:  GPNMB; Renal cell carcinoma; TFE3; TFEB; TSC1/2; angiomyolipoma; translocation renal cell carcinoma
    DOI:  https://doi.org/10.1002/path.5875
  7. Hautarzt. 2022 Feb;73(2): 114-126
    [Syndroms associated with benign skin tumors].
    George-Sorin Tiplica, Klaus Fritz, Alexandra Irina Butacu, Loredana Ungureanu, Carmen Maria Sălăvăstru.
      Benign skin tumors represent a wide category of diseases. The diagnosis is usually provided by the clinical aspect and the patient history. The pathological examination is not always considered necessary and in most cases the treatment is removal of the lesion by cryotherapy, electrosurgery or laser ablation. Deep phenotyping, including genetic and epigenetic findings, provided the basis of a new understanding of the pathogenetic mechanisms. Some benign skin tumors can be part of syndromes and the dermatologist should be aware of the extracutaneous associations defining these rare disorders: epidermal nevus can be associated with vascular malformations; nevus sebaceous can be associated with cerebral, ocular, and skeletal defects; nevus Becker is associated with cerebral, ocular, and skeletal defects; pilomatricomas appear earlier than colorectal cancer in Gardner's syndrome; tuberous sclerosis complex can associate not only central nervous system lesions but also pulmonary, cardiac or renal manifestations.
    Keywords:  Epidermal nevus syndromes; Neurofibromatosis type 1; Nevus comedonicus syndrome; Pseudoxanthoma elasticum; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1007/s00105-022-04947-0
  8. Fish Shellfish Immunol. 2022 Jan 22. pii: S1050-4648(22)00034-1. [Epub ahead of print]
    TBC domain family 7-like enhances the tolerance of Penaeus vannamei to ammonia nitrogen by the up-regulation of autophagy.
    Feifei Wang, Lin Huang, Qingjian Liang, Meiqiu Liao, Can Liu, Wenna Dong, Xueqi Zhuang, Xiaoli Yin, Yuan Liu, Weina Wang.
      TBC domain family 7 (TBC1D7) is one of the subunits of tuberous sclerosis complex (TSC) and an important regulator of autophagosome biogenesis. However, the function of TBC1D7 is not fully understood in crustaceans. In the present study, TBC1D7 was identified from Penaeus vannamei. The complete coding sequence of PvTBC1D7 was of 960 bp encoding a predicted polypeptide of 319 amino acids with one conserved TBC domain, which shared high similarity with TBC1D7 of that other species. The mRNA of PvTBC1D7 was highly expressed in hemocyte and hepatopancreas, and the PvTBC1D7 protein was localized specifically in the cytoplasm of hemocyte of shrimp. Besides, PvTBC1D7 was co-localized with PvTSC1 in the cytoplasm of shrimp, indicating that there might existed a binding relationship between PvTBC1D7 and PvTSC1. During the ammonia nitrogen stress, the mRNA transcripts of PvTBC1D7 were significantly upregulated in hemocyte, hepatopancreas, and gill. Functionally, overexpression of PvTBC1D7 in vitro restored the inhibition to autophagy caused by chloroquine (CLQ) and increased the autophagy level, while the silencing of PvTBC1D7 could inhibit the autophagy. More importantly, after interfering with PvTBC1D7, the autophagy level decreased significantly both in hepatopancreas and hemocyte of P. vannamei, the mRNA expression of PvmTOR was increased remarkably with the significantly decrease of autophagy-related genes (PvATG12 and PvATG14). And the reduction of PvTBC1D7 remarkably exacerbated the damage of hepatopancreas, increased the accumulation of ROS, and reduced the survival proportion of shrimp under ammonia nitrogen stress. Altogether, these results indicated that PvTBC1D7 might positively regulate the autophagy by stabilizing the negative regulation of mTOR by TSC complex, reduce the oxidative stress damage and improve shrimp ammonia nitrogen tolerance.
    Keywords:  Ammonia nitrogen; Autophagy; Penaeus vannamei; PvTBC1D7; PvTSC1
    DOI:  https://doi.org/10.1016/j.fsi.2022.01.025
  9. BMC Cancer. 2022 Jan 25. 22(1): 105
    The mixed blessing of AMPK signaling in Cancer treatments.
    Mehrshad Sadria, Deokhwa Seo, Anita T Layton.
       BACKGROUND: Nutrient acquisition and metabolism pathways are altered in cancer cells to meet bioenergetic and biosynthetic demands. A major regulator of cellular metabolism and energy homeostasis, in normal and cancer cells, is AMP-activated protein kinase (AMPK). AMPK influences cell growth via its modulation of the mechanistic target of Rapamycin (mTOR) pathway, specifically, by inhibiting mTOR complex mTORC1, which facilitates cell proliferation, and by activating mTORC2 and cell survival. Given its conflicting roles, the effects of AMPK activation in cancer can be counter intuitive. Prior to the establishment of cancer, AMPK acts as a tumor suppressor. However, following the onset of cancer, AMPK has been shown to either suppress or promote cancer, depending on cell type or state.
    METHODS: To unravel the controversial roles of AMPK in cancer, we developed a computational model to simulate the effects of pharmacological maneuvers that target key metabolic signalling nodes, with a specific focus on AMPK, mTORC, and their modulators. Specifically, we constructed an ordinary differential equation-based mechanistic model of AMPK-mTORC signaling, and parametrized the model based on existing experimental data.
    RESULTS: Model simulations were conducted to yield the following predictions: (i) increasing AMPK activity has opposite effects on mTORC depending on the nutrient availability; (ii) indirect inhibition of AMPK activity through inhibition of sirtuin 1 (SIRT1) only has an effect on mTORC activity under conditions of low nutrient availability; (iii) the balance between cell proliferation and survival exhibits an intricate dependence on DEP domain-containing mTOR-interacting protein (DEPTOR) abundance and AMPK activity; (iv) simultaneous direct inhibition of mTORC2 and activation of AMPK is a potential strategy for suppressing both cell survival and proliferation.
    CONCLUSIONS: Taken together, model simulations clarify the competing effects and the roles of key metabolic signalling pathways in tumorigenesis, which may yield insights on innovative therapeutic strategies.
    Keywords:  AMPK; Cancer; Dynamical system; Metabolism; mTORC
    DOI:  https://doi.org/10.1186/s12885-022-09211-1
  10. Mol Biol Rep. 2022 Jan 27.
    The impact of DAPK1 and mTORC1 signaling association on autophagy in cancer.
    Parvaneh Movahhed, Mohammadreza Saberiyan, Amir Safi, Zahra Arshadi, Faranak Kazerouni, Hossein Teimori.
       BACKGROUND: The autophagy pathway is used by eukaryotic cells to maintain metabolic homeostasis. Autophagy has two functions in cancerous cells which could inhibit tumorigenesis or lead to cancer progression by increasing cell survival and proliferation.
    METHODS AND RESULTS: In this review article, Web of Science, PubMed, Scopus,  and Google Scholar were searched and summarized published studies to explore the relationship between DAPK1 and mTORC1 signaling association on autophagy in cancer. Autophagy is managed through various proteins including the mTOR, which is two separated structural and functional complexes known as mTORC1 and mTORC2. MTORC1 is an important component of the regulatory pathway affecting numerous cellular functions including proliferation, migration, invasion, and survival. This protein plays a key role in human cancers. The activity level of mTORC1 is regulated by the death-associated protein kinases (DAPks) family, especially DAPK1. In many cancers, DAPK1 acts as a tumor suppressor which can be attributed to its ability to suppress cellular transformation and to inhibit metastasis.
    CONCLUSIONS: A deep investigation not only will reveal more about the function of DAPK1 but also might provide insights into novel therapies aimed to modulate the autophagy pathway in cancer and to achieve better cancer therapy.
    Keywords:  Autophagy; Cancer; DAPK1; mTORC1
    DOI:  https://doi.org/10.1007/s11033-022-07154-1
  11. J Pathol. 2022 Jan 23.
    Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2-Cre mice.
    Jason A Hanna, Casey G Langdon, Matthew R Garcia, Annaleigh Benton, Nadia A Lanman, David Finkelstein, Jerold E Rehg, Mark E Hatley.
      Angiosarcomas are aggressive vascular sarcomas that arise from endothelial cells and have an extremely poor prognosis. Because of the rarity of angiosarcoma, knowledge of molecular drivers and optimized treatment strategies are lacking, highlighting the need for in vivo models to study the disease. Previously, we generated genetically engineered mouse models of angiosarcoma driven by aP2-Cre-mediated biallelic loss of Dicer1 or conditional activation of KrasG12D with Cdkn2a loss that histologically and genetically resemble human tumors. Here, we find that DICER1 functions as a potent tumor suppressor and its deletion, in combination with either KRASG12D expression or Cdkn2a loss, is associated with angiosarcoma development. Independent of the genetic driver, the mTOR pathway was activated in all murine angiosarcoma models. Direct activation of the mTOR pathway by conditional deletion of Tsc1 with aP2-Cre resulted in tumors that resemble intermediate grade human kaposiform hemangioendotheliomas indicating that mTOR activation was not sufficient to drive the malignant angiosarcoma phenotype. Genetic dissection of the spectrum of vascular tumors identified genes specifically regulated in the aggressive murine angiosarcomas that are also enriched in human angiosarcoma. The genetic dissection driving the transition across the malignant spectrum of endothelial sarcomas provides an opportunity to identify key determinants of the malignant phenotype, novel therapies for angiosarcoma, and novel in vivo models to further explore angiosarcoma pathogenesis. This article is protected by copyright. All rights reserved.
    Keywords:  DICER1; TSC1; angiosarcoma; kaposiform hemangioendothelioma; sarcoma
    DOI:  https://doi.org/10.1002/path.5873
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