Erik Y. Zhang

University of Cincinnati

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Jane Yu

University of Auckland

Yan Xu

Peking Union Medical College Hospital

Francis X. McCormack

University of Cincinnati Medical Center

Minzhe Guo

Cincinnati Children's Hospital Medical Center

Kathryn A. Wikenheiser‐Brokamp

Cincinnati Children's Hospital Medical Center

Elizabeth J. Kopras

University of Cincinnati

Aristotelis Astrinidis

University of Cincinnati

Jeffrey A. Whitsett

Cincinnati Children's Hospital Medical Center

Eric P. Smith

University of Cincinnati Medical Center

David J. Kwiatkowski

Harvard University

Cooperative Institutions

University of Cincinnati

University of Cincinnati Medical Center

Cincinnati Children's Hospital Medical Center

Harvard University

Brigham and Women's Hospital

University of Pennsylvania

University of Tennessee Health Science Center

Perinatal Institute

Sabin Vaccine Institute

Chinese Academy of Sciences

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Identification of the Lymphangioleiomyomatosis Cell and Its Uterine Origin

SSRN Electronic Journal (2019)

Minzhe Guo Jane Yu Anne‐Karina T. Perl Kathryn A. Wikenheiser‐Brokamp Matthew Riccetti

Lymphangioleiomyomatosis (LAM) is a metastasizing neoplasm of reproductive age women that causes cystic lung remodeling and progressive respiratory failure. The source of LAM cells that invade the lung and the reasons that LAM targets women have remained elusive. We employed single cell and single nuclei RNA sequencing on LAM lesions within explanted LAM lungs, known to contain smooth muscle like cells bearing mTOR activating mutations in TSC1 or TSC2, and identified a unique population of cells that were readily distinguished from those of endogenous lung cells. LAM CORE cells shared closest transcriptomic similarity to normal uterus and neural crest. Immunofluorescence microscopy demonstrated the expression of LAMCORE cell signature genes within LAM lesions in both lung and uterus. Serum aptamer proteomics and ELISA identified biomarkers predicted to be secreted by LAM CORE cells. Single cell transcriptomics strongly supports a uterine neural crest origin of LAM CORE cells; providing insights into disease pathogenesis and informing future treatment strategies for LAM.

Lymphangioleiomyomatosis

Identification

10.2139/ssrn.3461777

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Citations (1)

Inhibition of the mechanistic target of rapamycin induces cell survival via MAPK in tuberous sclerosis complex

Orphanet Journal of Rare Diseases (2020)

Yiyang Lu Erik Y. Zhang Jie Liu Jane Yu

Abstract Background Tuberous sclerosis complex (TSC) is a genetic disorder that cause tumors to form in many organs. These lesions may lead to epilepsy, autism, developmental delay, renal, and pulmonary failure. Loss of function mutations in TSC1 and TSC2 genes by aberrant activation of the mechanistic target of rapamycin (mTORC1) signaling pathway are the known causes of TSC. Therefore, targeting mTORC1 becomes a most available therapeutic strategy for TSC. Although mTORC1 inhibitor rapamycin and Rapalogs have demonstrated exciting results in the recent clinical trials, however, tumors rebound and upon the discontinuation of the mTORC1 inhibition. Thus, understanding the underlying molecular mechanisms responsible for rapamycin-induced cell survival becomes an urgent need. Identification of additional molecular targets and development more effective remission-inducing therapeutic strategies are necessary for TSC patients. Results We have discovered an Mitogen-activated protein kinase (MAPK)-evoked positive feedback loop that dampens the efficacy of mTORC1 inhibition. Mechanistically, mTORC1 inhibition increased MEK1-dependent activation of MAPK in TSC-deficient cells. Pharmacological inhibition of MAPK abrogated this feedback loop activation. Importantly, the combinatorial inhibition of mTORC1 and MAPK induces the death of TSC2-deficient cells. Conclusions Our results provide a rationale for dual targeting of mTORC1 and MAPK pathways in TSC and other mTORC1 hyperactive neoplasm.

TSC2

TSC1

10.1186/s13023-020-01490-w

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Citations (8)

Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells

Science Advances (2023)

Tasnim Olatoke Andrew Wagner Aristotelis Astrinidis Erik Y. Zhang Minzhe Guo

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that predominantly affects women. LAM cells carry

Lymphangioleiomyomatosis

TSC1

10.1126/sciadv.adf8549

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Citations (5)

Rapamycin-Resistant Poly (ADP-Ribose) Polymerase-1 Overexpression Is a Potential Therapeutic Target in Lymphangioleiomyomatosis

American Journal of Respiratory Cell and Molecular Biology (2014)

Yang Sun Dana A. Gallacchi Erik Y. Zhang Samuel B Reynolds Lauren Robinson

Section:ChooseTop of pageAbstract <

Lymphangioleiomyomatosis

10.1165/rcmb.2014-0033oc

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Citations (11)

Combination of Volasertib and Rapamycin Inhibits the Regrowth of TSC2-Deficient Tumors

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Matthildi Valianou Erik Y. Zhang Daniel L. Johnson Rhett Meyers Maciej M. Markiewski

ABSTRACT Mutations in TSC1 and TSC2 lead to hyperactivation of mTORC1 and cause Tuberous Sclerosis Complex (TSC) and pulmonary Lymphangioleiomyomatosis (LAM). Rapamycin and rapalogs are potent inhibitors of mTORC1 activity and are approved for the treatment of TSC and LAM. Nevertheless, rapalogs do not cause tumor cell death, and cessation of therapy leads to tumor regrowth. Polo-like kinase 1 (PLK1) interacts with and phosphorylates TSC1, and PLK1 inhibition induces apoptosis and attenuates autophagy in TSC1/TSC2-deficient cells. Here we report that the PLK1 inhibitor volasertib decreases the viability and survival and induces apoptosis in 621-101 cells, a TSC-deficient renal angiomyolipoma cell line from a LAM patient. Combined with rapamycin, volasertib further decreased the survival of 621-101 cells. In vivo , volasertib reduced short-term mouse lung colonization by TSC2-deficient cells and decreased the growth of TSC2-deficient subcutaneous tumors. Mice treated with a combination of volasertib and rapamycin had slower tumor relapse after discontinuation of treatment, compared to rapamycin only. Approximately 35 days after discontinuation of treatment, we observed persistent apoptotic markers and gene expression changes for type I interferon signaling in the regrowth tumors from combination-treated mice, compared to rapamycin only. Notably, combination treatment potently inhibited the growth of subcutaneous tumors derived from the rapamycin-refractory cell line ELT3-245. Taken together, our current work demonstrates that for the management of TSC and LAM disease combination of mTORC1 and PLK1 inhibitors in some cases may be advantageous over currently used rapalog monotherapies.

TSC1

Lymphangioleiomyomatosis

TSC2

Sirolimus

PLK1

10.1101/2022.11.02.512640

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

JCI Insight (2023)

Aristotelis Astrinidis Chenggang Li Erik Y. Zhang Xueheng Zhao Shuyang Zhao

Tuberous sclerosis complex (TSC) is characterized by multisystem, 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 result 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 mechanistic target of rapamycin complex 1-hyperactive neoplasms, including TSC and LAM.

TSC2

Sphingolipid

TSC1

10.1172/jci.insight.166850

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Citations (3)

Dysregulation of Acid Ceramidase-mediated Sphingolipid Metabolism Contributes to Tumor Progression in Tuberous Sclerosis Complex

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Aristotelis Astrinidis Chenggang Li Erik Y. Zhang Xueheng Zhao Shuyang Zhao

Abstract Tuberous Sclerosis Complex (TSC) is disorder of multi-system benign neoplasia in the brain, heart, kidneys and lungs. Lymphangioleiomyomatosis (LAM) is a progressive pulmonary disease affecting exclusively women. Both are caused by mutations in TSC1 and TSC2 , resulting in mTORC1 hyperactivation. Single cell RNA sequencing of LAM lungs identified activation of genes in the sphingolipid pathway. Independent validation studies showed that acid ceramidase ( ASAH1 ) and dihydroceramide desaturase ( DEGS1 ), key enzyme for regulating sphingolipid and ceramide metabolism, were significantly increased in TSC2-null cells, and their expression and activity were rapamycin-insensitive. TSC2 negatively regulated the biosynthesis of tumorigenic sphingolipids. Suppression of ASAH1 by shRNA or the inhibitor ARN14976 (17a) markedly decreased the viability of TSC2-null cells. In vivo , 17a significantly decreased the growth of Tsc2-null cell derived mouse xenografts. When combined with rapamycin, 17a more strongly inhibited the progression of renal cystadenomas in Tsc2 +/- mice than either agent alone, evaluated by pathology and MRI. Collectively, our studies identify a rapamycin-insensitive disorder of sphingolipid metabolism in TSC2-null cells and tumors and validate the novel hypothesis that TSC2 regulates sphingolipid production and action via ASAH1. Targeting aberrant sphingolipid metabolism pathways may have therapeutic value in TSC and LAM, and possibly in mTORC1-hyperactive neoplasms.

Sphingolipid

TSC2

TSC1

10.1101/2022.09.25.509382

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Citations (0)

Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis

JCI Insight (2016)

Chenggang Li Na Li Xiaolei Liu Erik Y. Zhang Yang Sun

Lymphangioleiomyomatosis (LAM) is a progressive lung disease that primarily affects young women. Genetic evidence suggests that LAM cells bearing

Anoikis

Lymphangioleiomyomatosis

10.1172/jci.insight.86629

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Citations (10)

Connectivity analysis of single cell RNA-sequencing derived transcriptional signature of lymphangioleiomyomatosis

bioRxiv (Cold Spring Harbor Laboratory) (2020)

Naim Al Mahi Erik Y. Zhang Susan G. Sherman Jane Yu Mario Medvedovic

ABSTRACT Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease affecting women of childbearing age that is characterized by the aberrant proliferation of smooth-muscle (SM)-like cells and emphysema-like lung remodeling. In LAM, mutations in TSC1 or TSC2 genes results in the activation of the mechanistic target of rapamycin complex 1 (mTORC1) and thus sirolimus, an mTORC1 inhibitor, has been approved by FDA to treat LAM patients. Sirolimus stabilizes lung function and improves symptoms. However, the disease recurs with discontinuation of the drug, potentially because of the sirolimus-induced refractoriness of the LAM cells. Therefore, there is a critical need to identify remission inducing cytocidal treatments for LAM. Recently released Library of Integrated Network-based Cellular Signatures (LINCS) L1000 transcriptional signatures of chemical perturbations has opened new avenues to study cellular responses to existing drugs and new bioactive compounds. Connecting transcriptional signature of a disease to these chemical perturbation signatures to identify bioactive chemicals that can “revert” the disease signatures can lead to novel drug discovery. We developed methods for constructing disease transcriptional signatures and performing connectivity analysis using single cell RNA-seq data. The methods were applied in the analysis of scRNA-seq data of naïve and sirolimus-treated LAM cells. The single cell connectivity analyses implicated mTORC1 inhibitors as capable of reverting the LAM transcriptional signatures while the corresponding standard bulk analysis did not. This indicates the importance of using single cell analysis in constructing disease signatures. The analysis also implicated other classes of drugs, CDK, MEK/MAPK and EGFR/JAK inhibitors, as potential therapeutic agents for LAM.

Lymphangioleiomyomatosis

Sirolimus

TSC1

10.1101/2020.09.30.320473

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Citations (1)

Identification of the lymphangioleiomyomatosis cell and its uterine origin

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Minzhe Guo Jane Yu Anne‐Karina T. Perl Kathryn A. Wikenheiser‐Brokamp Matthew Riccetti

SUMMARY Lymphangioleiomyomatosis (LAM) is a metastasizing neoplasm of reproductive age women that causes cystic lung remodeling and progressive respiratory failure. The source of LAM cells that invade the lung and the reasons that LAM targets women have remained elusive. We employed single cell and single nuclei RNA sequencing on LAM lesions within explanted LAM lungs, known to contain smooth muscle like cells bearing mTOR activating mutations in TSC1 or TSC2, and identified a unique population of cells that were readily distinguished from those of endogenous lung cells. LAM CORE cells shared closest transcriptomic similarity to normal uterus and neural crest. Immunofluorescence microscopy demonstrated the expression of LAM CORE cell signature genes within LAM lesions in both lung and uterus. Serum aptamer proteomics and ELISA identified biomarkers predicted to be secreted by LAM CORE cells. Single cell transcriptomics strongly supports a uterine neural crest origin of LAM CORE cells; providing insights into disease pathogenesis and informing future treatment strategies for LAM. SIGNIFICANCE Present study identified a novel population of LAM CORE cells, which is likely originated from uterine neural crest; identified novel LAM cell-specific secretome proteins that hold promise as potential biomarkers and therapeutic targets. Advancing the understanding of LAM pathogenesis and metastasis model may yield broader insights into the biology of cancer.

Lymphangioleiomyomatosis

Pathogenesis

TSC1

10.1101/784199

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Citations (4)