Emerging Concepts in Pathogenesis, Multiomics Applications, and Clinical Research in Lymphangioleiomyomatosis

Jane J. Yu; Nishant Gupta; Minzhe Guo; Tasnim Olatoke; Yan Xu

doi:10.1055/a-2698-7273

Seminars in Respiratory and Critical Care Medicine, Table of Contents

Semin Respir Crit Care Med
DOI: 10.1055/a-2698-7273

Review Article

Emerging Concepts in Pathogenesis, Multiomics Applications, and Clinical Research in Lymphangioleiomyomatosis

Authors

Jane J. Yu

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
Nishant Gupta

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
Minzhe Guo

²The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio
Tasnim Olatoke

¹Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
Yan Xu

²The Perinatal Institute and Section of Neonatology, Perinatal and Pulmonary Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio

³Department of Biomedical Informatics, University of Cincinnati School of Medicine, Cincinnati, Ohio

Abstract

Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm characterized by infiltration of abnormal smooth muscle-like and epithelioid cells into the lung parenchyma, leading to cystic changes and progressive respiratory failure. In recent years, LAM has been an exemplar of meaningful progress in a rare lung disease, driven by close collaboration between patients, scientists, and clinicians, leading to the development of the U.S. Food and Drug Administration (FDA)-approved therapy, a diagnostic biomarker, a worldwide clinic network, and clinical practice guidelines. Integrating state-of-the-art bioinformatics and experimental approaches is helping accelerate the scientific progress in LAM and promises the development of novel biomarkers and therapies in the coming few years.

Keywords

lymphangioleiomyomatosis - diagnostic biomarker - progressive respiratory failure - bioinformatics applications in LAM

Full Text

References

References
1 Olatoke T, Wagner A, Astrinidis A. et al. Single-cell multiomic analysis identifies a HOX-PBX gene network regulating the survival of lymphangioleiomyomatosis cells. Sci Adv 2023; 9 (19) eadf8549
2 McCarthy C, Gupta N, Johnson SR, Yu JJ, McCormack FX. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management. Lancet Respir Med 2021; 9 (11) 1313-1327
3 McCormack FX, Travis WD, Colby TV, Henske EP, Moss J. Lymphangioleiomyomatosis: calling it what it is: a low-grade, destructive, metastasizing neoplasm. Am J Respir Crit Care Med 2012; 186 (12) 1210-1212
4 Gupta N, Johnson SR. Lymphangioleiomyomatosis: No longer ultra-rare. Am J Respir Crit Care Med 2024; 209 (04) 358-359
5 Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A 2000; 97 (11) 6085-6090
6 Guo M, Yu JJ, Perl AK. et al. Single-cell transcriptomic analysis identifies a unique pulmonary lymphangioleiomyomatosis cell. Am J Respir Crit Care Med 2020; 202 (10) 1373-1387
7 Plank TL, Yeung RS, Henske EP. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res 1998; 58 (21) 4766-4770
8 Dibble CC, Elis W, Menon S. et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 2012; 47 (04) 535-546
9 Garami A, Zwartkruis FJ, Nobukuni T. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003; 11 (06) 1457-1466
10 Stocker H, Radimerski T, Schindelholz B. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila . Nat Cell Biol 2003; 5 (06) 559-565
11 Valvezan AJ, Turner M, Belaid A. et al. mTORC1 couples nucleotide synthesis to nucleotide demand resulting in a targetable metabolic vulnerability. Cancer Cell 2017; 32 (05) 624-638.e5
12 Alayev A, Salamon RS, Sun Y. et al. Effects of combining rapamycin and resveratrol on apoptosis and growth of TSC2-deficient xenograft tumors. Am J Respir Cell Mol Biol 2015; 53 (05) 637-646
13 Alayev A, Sun Y, Snyder RB, Berger SM, Yu JJ, Holz MK. Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells. Cell Cycle 2014; 13 (03) 371-382
14 Lam HC, Baglini CV, Lope AL. et al. p62/SQSTM1 cooperates with hyperactive mTORC1 to regulate glutathione production, maintain mitochondrial integrity, and promote tumorigenesis. Cancer Res 2017; 77 (12) 3255-3267
15 Parkhitko A, Myachina F, Morrison TA. et al. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proc Natl Acad Sci U S A 2011; 108 (30) 12455-12460
16 Parkhitko AA, Priolo C, Coloff PL. et al. Autophagy-dependent metabolic reprogramming sensitizes TSC2-deficient cells to the antimetabolite 6-aminonicotinamide. Mol Cancer Res 2014; 12: 48-57
17 Alesi N, Akl EW, Khabibullin D. et al. TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism. Nat Commun 2021; 12 (01) 4245
18 Filippakis H, Belaid A, Siroky B. et al. Vps34-mediated macropinocytosis in Tuberous Sclerosis Complex 2-deficient cells supports tumorigenesis. Sci Rep 2018; 8 (01) 14161
19 Ancona S, Orpianesi E, Bernardelli C. et al. Differential modulation of matrix metalloproteinases-2 and -7 in LAM/TSC cells. Biomedicines 2021; 9 (12) 1760
20 Chang WY, Clements D, Johnson SR. Effect of doxycycline on proliferation, MMP production, and adhesion in LAM-related cells. Am J Physiol Lung Cell Mol Physiol 2010; 299 (03) L393-L400
21 Lee PS, Tsang SW, Moses MA. et al. Rapamycin-insensitive up-regulation of MMP2 and other genes in tuberous sclerosis complex 2-deficient lymphangioleiomyomatosis-like cells. Am J Respir Cell Mol Biol 2010; 42 (02) 227-234
22 Li C, Zhou X, Sun Y. et al. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2013; 49 (01) 135-142
23 Matsui K, Takeda K, Yu ZX, Travis WD, Moss J, Ferrans VJ. Role for activation of matrix metalloproteinases in the pathogenesis of pulmonary lymphangioleiomyomatosis. Arch Pathol Lab Med 2000; 124 (02) 267-275
24 Moir LM, Ng HY, Poniris MH. et al. Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells. Br J Pharmacol 2011; 164 (01) 83-92
25 Odajima N, Betsuyaku T, Nasuhara Y, Inoue H, Seyama K, Nishimura M. Matrix metalloproteinases in blood from patients with LAM. Respir Med 2009; 103 (01) 124-129
26 Gibbons E, Taya M, Wu H. et al. Glycoprotein non-metastatic melanoma protein B promotes tumor growth and is a biomarker for lymphangioleiomyomatosis. Endocr Relat Cancer 2024; 31 (06) e230312
27 Dodd KM, Yang J, Shen MH, Sampson JR, Tee AR. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 2015; 34 (17) 2239-2250
28 Young L, Lee HS, Inoue Y. et al; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med 2013; 1 (06) 445-452
29 Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med 2008; 358 (02) 199-200
30 Ma D, Bai X, Zou H, Lai Y, Jiang Y. Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL. J Biol Chem 2010; 285 (12) 8621-8627
31 Mutvei AP, Nagiec MJ, Hamann JC, Kim SG, Vincent CT, Blenis J. Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability. Nat Commun 2020; 11 (01) 1416
32 Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011; 13 (02) 132-141
33 Li C, Li N, Liu X. et al. Proapoptotic protein Bim attenuates estrogen-enhanced survival in lymphangioleiomyomatosis. JCI Insight 2016; 1 (19) e86629
34 Goncharova EA, Goncharov DA, Li H. et al. mTORC2 is required for proliferation and survival of TSC2-null cells. Mol Cell Biol 2011; 31 (12) 2484-2498
35 Li C, Lee PS, Sun Y. et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med 2014; 211 (01) 15-28
36 Liu HJ, Du H, Khabibullin D. et al. mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion. Nat Commun 2023; 14 (01) 1214
37 Babaei-Jadidi R, Dongre A, Miller S. et al. Mast-cell tryptase release contributes to disease progression in lymphangioleiomyomatosis. Am J Respir Crit Care Med 2021; 204 (04) 431-444
38 Osterburg AR, Nelson RL, Yaniv BZ. et al. NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline. JCI Insight 2016; 1 (16) e87270
39 Liu HJ, Diesler R, Chami J. et al. Modulation of infiltrating CD206-positive macrophages restricts progression of pulmonary lymphangioleiomyomatosis (LAM). Eur Respir J 2025; 2500084
40 Astrinidis A, Li C, Zhang EY. et al. Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex. JCI Insight 2023; 8 (09) e166850
41 Li F, Zhang Y, Lin Z. et al. Targeting SPHK1/S1PR3-regulated S-1-P metabolic disorder triggers autophagic cell death in pulmonary lymphangiomyomatosis (LAM). Cell Death Dis 2022; 13 (12) 1065
42 Li C, Liu X, Liu Y. et al. Tuberin regulates prostaglandin receptor-mediated viability, via Rheb, in mTORC1-hyperactive cells. Mol Cancer Res 2017; 15 (10) 1318-1330
43 Li C, Zhang E, Sun Y. et al. Rapamycin-insensitive up-regulation of adipocyte phospholipase A2 in tuberous sclerosis and lymphangioleiomyomatosis. PLoS One 2014; 9 (10) e104809
44 Priolo C, Ricoult SJ, Khabibullin D. et al. Tuberous sclerosis complex 2 loss increases lysophosphatidylcholine synthesis in lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2015; 53 (01) 33-41
45 Olatoke T, Zhang E, Wagner A. et al. STAT1 promotes PD-L1 activation and tumor growth in lymphangioleiomyomatosis. bioRxiv 2024
46 Liu HJ, Krymskaya VP, Henske EP. Immunotherapy for lymphangioleiomyomatosis and tuberous sclerosis: progress and future directions. Chest 2019; 156 (06) 1062-1067
47 Liu HJ, Lizotte PH, Du H. et al. TSC2-deficient tumors have evidence of T cell exhaustion and respond to anti-PD-1/anti-CTLA-4 immunotherapy. JCI Insight 2018; 3 (08) e98674
48 Maisel K, Merrilees MJ, Atochina-Vasserman EN. et al. Immune checkpoint ligand PD-L1 is upregulated in pulmonary lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2018; 59 (06) 723-732
49 Harknett EC, Chang WY, Byrnes S. et al. Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis. QJM 2011; 104 (11) 971-979
50 Lynn E, Forde SH, Franciosi AN. et al; Northern European LAM Prevalence Consortium. Updated prevalence of lymphangioleiomyomatosis in Europe. Am J Respir Crit Care Med 2024; 209 (04) 456-459
51 Kimura Y, Jo T, Hashimoto Y. et al. Epidemiology of patients with lymphangioleiomyomatosis: A descriptive study using the national database of health insurance claims and specific health checkups of Japan. Respir Investig 2024; 62 (03) 494-502
52 Shaw BM, Kopras E, Gupta N. Menstrual cycle-related respiratory symptom variability in patients with lymphangioleiomyomatosis. Ann Am Thorac Soc 2022; 19 (09) 1619-1621
53 Rubin R, Baldi BG, Shaw BM. et al. Hemoptysis associated with sexual activity in lymphangioleiomyomatosis. Ann Am Thorac Soc 2024; 21 (12) 1784-1787
54 McCormack FX, Gupta N, Finlay GR. et al; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med 2016; 194 (06) 748-761
55 McCormack FX, Inoue Y, Moss J. et al; National Institutes of Health Rare Lung Diseases Consortium, MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364 (17) 1595-1606
56 Bissler JJ, McCormack FX, Young LR. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358 (02) 140-151
57 Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J. Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 2011; 154 (12) 797-805 , W-292–W-293
58 Ando K, Kurihara M, Kataoka H. et al. Efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis. Respir Investig 2013; 51 (03) 175-183
59 Bee J, Fuller S, Miller S, Johnson SR. Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study. Thorax 2018; 73 (04) 369-375
60 Cortinas N, Liu J, Kopras E, Memon H, Burkes R, Gupta N. Impact of age, menopause, and sirolimus on spontaneous pneumothoraces in lymphangioleiomyomatosis. Chest 2022; 162 (06) 1324-1327
61 Zhou L, Ouyang R, Luo H. et al. Efficacy of sirolimus for the prevention of recurrent pneumothorax in patients with lymphangioleiomyomatosis: a case series. Orphanet J Rare Dis 2018; 13 (01) 168
62 Xu W, Yang C, Cheng C. et al. Determinants of progression and mortality in lymphangioleiomyomatosis. Chest 2023; 164 (01) 137-148
63 Taveira-DaSilva AM, Johnson SR, Julien-Williams P, Johnson J, Stylianou M, Moss J. Pregnancy in lymphangioleiomyomatosis: clinical and lung function outcomes in two national cohorts. Thorax 2020; 75 (10) 904-907
64 Munshi A, Hyslop AD, Kopras EJ, Gupta N. Spontaneous pneumothoraces during pregnancy in patients with lymphangioleiomyomatosis. Respir Investig 2023; 61 (05) 632-635
65 Krishna R, Johnson SR, Ataya A. et al. Sirolimus use during pregnancy in women with lymphangioleiomyomatosis. Ann Am Thorac Soc 2025; (E-pub ahead of print)
66 Palipana AK, Gecili E, Song S, Johnson SR, Szczesniak RD, Gupta N. Predicting individualized lung disease progression in treatment-naive patients with lymphangioleiomyomatosis. Chest 2023; 163 (06) 1458-1470
67 Hao Y, Stuart T, Kowalski MH. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat Biotechnol 2024; 42 (02) 293-304
68 Ma A, McDermaid A, Xu J, Chang Y, Ma Q. Integrative methods and practical challenges for single-cell multi-omics. Trends Biotechnol 2020; 38 (09) 1007-1022
69 Moses L, Pachter L. Museum of spatial transcriptomics. Nat Methods 2022; 19 (05) 534-546
70 Hao Y, Hao S, Andersen-Nissen E. et al. Integrated analysis of multimodal single-cell data. Cell 2021; 184 (13) 3573-3587.e29
71 Obraztsova K, Basil MC, Rue R. et al. mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline. Nat Commun 2020; 11 (01) 5640
72 Minor BMN, LeMoine D, Seger C. et al. Estradiol augments tumor-induced neutrophil production to promote tumor cell actions in lymphangioleiomyomatosis models. Endocrinology 2023; 164 (06) bqad061
73 Lin SM, Rue R, Mukhitov AR. et al. Hyperactive mTORC1 in lung mesenchyme induces endothelial cell dysfunction and pulmonary vascular remodeling. J Clin Invest 2023; 134 (04) e172116
74 Al Mahi N, Zhang EY, Sherman S, Yu JJ, Medvedovic M. Connectivity Map analysis of a single-cell RNA-sequencing-derived transcriptional signature of mTOR signaling. Int J Mol Sci 2021; 22 (09) 4371
75 Espín R, Baiges A, Blommaert E. et al. Heterogeneity and cancer-related features in lymphangioleiomyomatosis cells and tissue. Mol Cancer Res 2021; 19 (11) 1840-1853
76 Farré X, Espín R, Baiges A. et al. Evidence for shared genetic risk factors between lymphangioleiomyomatosis and pulmonary function. ERJ Open Res 2022; 8 (01) 00375-2021
77 Wang H, Hu D, Cheng C. et al. Synergistic effects of mTOR inhibitors with VEGFR3 inhibitors on the interaction between TSC2-mutated cells and lymphatic endothelial cells. Sci China Life Sci 2025; 68 (06) 1676-1688
78 Tang Y, Kwiatkowski DJ, Henske EP. Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment. Nat Commun 2022; 13 (01) 5018
79 Daley GQ. Stem cells and the evolving notion of cellular identity. Philos Trans R Soc Lond B Biol Sci 2015; 370 (1680): 20140376
80 Fiers MWEJ, Minnoye L, Aibar S, Bravo González-Blas C, Kalender Atak Z, Aerts S. Mapping gene regulatory networks from single-cell omics data. Brief Funct Genomics 2018; 17 (04) 246-254
81 Aibar S, González-Blas CB, Moerman T. et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods 2017; 14 (11) 1083-1086
82 Moerman T, Aibar Santos S, Bravo González-Blas C. et al. GRNBoost2 and Arboreto: efficient and scalable inference of gene regulatory networks. Bioinformatics 2019; 35 (12) 2159-2161
83 Bravo González-Blas C, De Winter S, Hulselmans G. et al. SCENIC+: single-cell multiomic inference of enhancers and gene regulatory networks. Nat Methods 2023; 20 (09) 1355-1367
84 Zhang L, Zhang J, Nie Q. DIRECT-NET: An efficient method to discover cis-regulatory elements and construct regulatory networks from single-cell multiomics data. Sci Adv 2022; 8 (22) eabl7393
85 Fleck JS, Jansen SMJ, Wollny D. et al. Inferring and perturbing cell fate regulomes in human brain organoids. Nature 2023; 621 (7978): 365-372
86 Kamimoto K, Stringa B, Hoffmann CM, Jindal K, Solnica-Krezel L, Morris SA. Dissecting cell identity via network inference and in silico gene perturbation. Nature 2023; 614 (7949): 742-751
87 Duren Z, Chen X, Xin J, Wang Y, Wong WH. Time course regulatory analysis based on paired expression and chromatin accessibility data. Genome Res 2020; 30 (04) 622-634
88 Guo M, Du Y, Gokey JJ. et al. Single cell RNA analysis identifies cellular heterogeneity and adaptive responses of the lung at birth. Nat Commun 2019; 10 (01) 37
89 Guo M, Wang H, Potter SS, Whitsett JA, Xu Y. SINCERA: A pipeline for single-cell RNA-seq profiling analysis. PLoS Comput Biol 2015; 11 (11) e1004575
90 Iacono G, Massoni-Badosa R, Heyn H. Single-cell transcriptomics unveils gene regulatory network plasticity. Genome Biol 2019; 20 (01) 110
91 Guo M, Xu Y. Single-cell transcriptome analysis using SINCERA pipeline. Methods Mol Biol 2018; 1751: 209-222
92 Gokey JJ, Snowball J, Sridharan A. et al. YAP regulates alveolar epithelial cell differentiation and AGER via NFIB/KLF5/NKX2-1. iScience 2021; 24 (09) 102967
93 Lo K, Raftery AE, Dombek KM. et al. Integrating external biological knowledge in the construction of regulatory networks from time-series expression data. BMC Syst Biol 2012; 6: 101
94 Nazri A, Lio P. Investigating meta-approaches for reconstructing gene networks in a mammalian cellular context. PLoS One 2012; 7 (01) e28713
95 Chan TE, Stumpf MPH, Babtie AC. Gene regulatory network inference from single-cell data using multivariate information measures. Cell Syst 2017; 5 (03) 251-267.e3
96 Sikkema L, Ramírez-Suástegui C, Strobl DC. et al; Lung Biological Network Consortium. An integrated cell atlas of the lung in health and disease. Nat Med 2023; 29 (06) 1563-1577
97 Williams CG, Lee HJ, Asatsuma T, Vento-Tormo R, Haque A. An introduction to spatial transcriptomics for biomedical research. Genome Med 2022; 14 (01) 68
98 Rao A, Barkley D, França GS, Yanai I. Exploring tissue architecture using spatial transcriptomics. Nature 2021; 596 (7871): 211-220
99 Chen TY, You L, Hardillo JAU, Chien MP. Spatial transcriptomic technologies. Cells 2023; 12 (16) 2042
100 He S, Bhatt R, Brown C. et al. High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging. Nat Biotechnol 2022; 40 (12) 1794-1806
101 Ståhl PL, Salmén F, Vickovic S. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 2016; 353 (6294): 78-82
102 Chen KH, Boettiger AN, Moffitt JR, Wang S, Zhuang X. RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells. Science 2015; 348 (6233): aaa6090
103 Koc-Gunel S, Liu EC, Gautam LK. et al. Targeting fibroblast-endothelial cell interactions in LAM pathogenesis using 3D spheroid models and spatial transcriptomics. JCI Insight 2025; 10 (06) e187899
104 Chen K, Zhao S, Guo M. et al. Decoding lymphangioleiomyomatosis (LAM) niche environment via integrative analysis of single cell multiomics and spatial transcriptomics. bioRxiv 2025
105 Guo M, Morley MP, Jiang C. et al; NHLBI LungMAP Consortium. Guided construction of single cell reference for human and mouse lung. Nat Commun 2023; 14 (01) 4566
106 Delorey TM, Ziegler CGK, Heimberg G. et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 2021; 595 (7865): 107-113
107 Du Y, Guo M, Wu Y. et al. Lymphangioleiomyomatosis (LAM) Cell Atlas. Thorax 2023; 78 (01) 85-87
108 Young LR, Vandyke R, Gulleman PM. et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138 (03) 674-681
109 Gupta N, Finlay GA, Kotloff RM. et al; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis diagnosis and management: High-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med 2017; 196 (10) 1337-1348
110 Johnson SR, Cordier JF, Lazor R. et al; Review Panel of the ERS LAM Task Force. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J 2010; 35 (01) 14-26
111 Holz MK, Slattery AD, Pontz EJ. et al. Lymphangioleiomyomatosis (LAM) Patient Research Priorities (LAM-PREP): Developing a patient-centered research agenda. CHEST Pulm 2025; 3: 100184
112 Wang Z, Liu X, Wang W. et al. A multi–omics study of diagnostic markers and the unique inflammatory tumor micro–environment involved in tuberous sclerosis complex–related renal angiomyolipoma. Int J Oncol 2022; 61 (05) 132
113 Huynh-Thu VA, Irrthum A, Wehenkel L, Geurts P. Inferring regulatory networks from expression data using tree-based methods. PLoS ONE 2010; 5 (09) e12776
114 Li Y, Liu X, Guo L. et al. SpaGRN: Investigating spatially informed regulatory paths for spatially resolved transcriptomics data. Cell Syst 2025; 16 (04) 101243
115 Wang Y, Zhou F, Guan J. SFINN: inferring gene regulatory network from single-cell and spatial transcriptomic data with shared factor neighborhood and integrated neural network. Bioinformatics 2024; 40 (07) btae433