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ResearchIn-Press PreviewCell biologyMetabolism Open Access | 10.1172/jci.insight.166850

Upregulation of acid ceramidase contributes to tumor progression in Tuberous Sclerosis Complex

Aristotelis Astrinidis,1 Chenggang Li,1 Erik Y. Zhang,1 Xueheng Zhao,2 Shuyang Zhao,3 Minzhe Guo,3 Tasnim Olatoke,1 Ushodaya Mattam,1 Rong Huang,4 Alan Zhang,1 Lori Pitstick,1 Elizabeth J. Kopras,1 Nishant Gupta,1 Roman A. Jandarov,5 Eric P. Smith,1 Elizabeth Fugate,6 Diana Lindquist,6 Maciej M. Markiewski,7 Magdalena Karbowniczek,8 Kathryn A. Wikenheiser-Brokamp,9 Kenneth D. Setchell,10 Francis X. McCormack,1 Yan Xu,11 and Jane Yu1

1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

Find articles by Astrinidis, A. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

Find articles by Li, C. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

Find articles by Zhang, E. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

Find articles by Mattam, U. in: JCI | PubMed | Google Scholar |

1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

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1Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, United States of America

2Division of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

3Divisions of Pulmonary Biology and Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

4Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

5Department of Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, United States of America

6Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America

7Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, United States of America

8Department of Immunotherapeutics and Biotechnology, Texas Tech Univsersity Health Sciences Center, Abilene, United States of America

9Division of Pathology and Laboratory Medicine, Division of Pulmonary Medici, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

10Division of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, United States of America

11Divisions of Pulmonary Biology and Biomedical Informatics, Perinatal Instit, Cincinnati Children's Hospital Medical Center, Cincinnati, United States of America

12Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinanti, United States of America

Find articles by Yu, J. in: JCI | PubMed | Google Scholar

Published March 16, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.166850.
Copyright © 2023, Astrinidis et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 16, 2023 - Version history
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Abstract

Tuberous Sclerosis Complex (TSC) is characterized by multi-system low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting almost exclusively women. TSC and LAM are both caused by mutations in TSC1 and TSC2 that results in mTORC1 hyperactivation. Here, we report that single-cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid biosynthesis pathway. Accordingly, the expression of acid ceramidase (ASAH1) and dihydroceramide desaturase (DEGS1), key enzymes controlling sphingolipid and ceramide metabolism, was significantly increased in TSC2-null cells. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids, and suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) resulted in markedly decreased TSC2-null cell viability. In vivo, 17a significantly decreased the growth of TSC2-null cell derived mouse xenografts and short-term lung colonization by TSC2-null cells. Combined rapamycin and 17a treatment synergistically inhibited renal cystadenoma growth in Tsc2+/- mice, consistent with increased ASAH1 expression and activity being rapamycin insensitive. Collectively, the present study identifies rapamycin-insensitive ASAH1 upregulation in TSC2-null cells and tumors and provides evidence that targeting aberrant sphingolipid biosynthesis pathways has potential therapeutic value in mTORC1-hyperactive neoplasms including TSC and LAM.

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