Needle in the Haystack: Finding the Elusive Lymphangioleiomyomatosis Cell

Steagall, Wendy K.; Moss, Joel

doi:10.1164/rccm.202006-2436ed

Cited by 2 publications

(6 citation statements)

References 15 publications

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“…LAM lesions also stain positively for melanocytic markers detected with HMB45 3,4 , chemoattractant proteins CCL2 and CXCL12 14 the lymphangiogenic factor VEGFD 15 , and also contain activated fibroblasts 16 . However, the origin or the evolution of the "bona fide" cell of disease origin in LAM is hotly debated [17][18][19] .…”

Section: Resultsmentioning

confidence: 99%

mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline

et al. 2020

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Lymphangioleiomyomatosis (LAM) is a rare fatal cystic lung disease due to bi-allelic inactivating mutations in tuberous sclerosis complex (TSC1/TSC2) genes coding for suppressors of the mechanistic target of rapamycin complex 1 (mTORC1). The origin of LAM cells is still unknown. Here, we profile a LAM lung compared to an age- and sex-matched healthy control lung as a hypothesis-generating approach to identify cell subtypes that are specific to LAM. Our single-cell RNA sequencing (scRNA-seq) analysis reveals novel mesenchymal and transitional alveolar epithelial states unique to LAM lung. This analysis identifies a mesenchymal cell hub coordinating the LAM disease phenotype. Mesenchymal-restricted deletion of Tsc2 in the mouse lung produces a mTORC1-driven pulmonary phenotype, with a progressive disruption of alveolar structure, a decline in pulmonary function, increase of rapamycin-sensitive expression of WNT ligands, and profound female-specific changes in mesenchymal and epithelial lung cell gene expression. Genetic inactivation of WNT signaling reverses age-dependent changes of mTORC1-driven lung phenotype, but WNT activation alone in lung mesenchyme is not sufficient for the development of mouse LAM-like phenotype. The alterations in gene expression are driven by distinctive crosstalk between mesenchymal and epithelial subsets of cells observed in mesenchymal Tsc2-deficient lungs. This study identifies sex- and age-specific gene changes in the mTORC1-activated lung mesenchyme and establishes the importance of the WNT signaling pathway in the mTORC1-driven lung phenotype.

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Section: Resultsmentioning

confidence: 99%

mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline

et al. 2020

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“…Inactivating mutations in genes encoding the TIE1 receptor that heterodimerizes with TIE2, or its ligand ANGPT2 lead to abnormal lymphatic development in mice 96 , and ANGPT2 mutations were recently implicated in lymphedema 97 . ANGPT2 protein has also been studied as a biomarker of lymphangioleiomyomatosis (LAM), which is a rare multisystem disease characterized by cystic destruction of the lungs and lymphatic involvement 98,99 , and of some CLAs 100,101 .…”

Section: Lymphangiogenic Signaling Pathways Implicated In Lymphatic A...mentioning

confidence: 99%

“…122 Another interesting observation is that in lymphangioleiomyomatosis, which is characterized by cystic destruction of the lungs, core lymphangioleiomyomatosis cells carrying inactivating mutations in TSC1 or TSC2 express high levels of the other VEGFR3 ligand, VEGF-D, and thereby recruit a coating by normal LECs that induce cysts in the lungs. 98,99 Direct cell-cell interaction between mutant and normal LECs may induce a phenotypic change in the latter and thereby promote their participation in the lesions. Interestingly, mosaic inactivation of VEGFR3 in LECs in mice promoted lymphatic vessel hyperplasia by activating proliferation of neighboring wild type LECs through cell-cell contact mediated regulation of NOTCH signaling, 46 thus revealing a noncell-autonomous (ie, not driven by cells targeted by the genetic alteration) mechanism driving pathological vessel growth.…”

Section: Future Therapeutic Directionsmentioning

confidence: 99%

“…Inactivating mutations in genes encoding the TIE1 receptor that heterodimerizes with TIE2, or its ligand ANGPT2 lead to abnormal lymphatic development in mice, 96 and ANGPT2 mutations were recently implicated in lymphedema. 97 ANGPT2 protein has also been studied as a biomarker of lymphangioleiomyomatosis, which is a rare multisystem disease characterized by cystic destruction of the lungs and lymphatic involvement, 98,99 and of some CLAs. 100,101 Interestingly, although the majority of venous malformations in humans are explained by activating mutations in TIE2 , 102 they have not been detected in lymphatic anomalies, whereas TIE1 is currently being considered as a candidate gene in LMs with or without lymphedema.…”

Section: Lymphangiogenic Signaling Pathways Implicated In Lymphatic A...mentioning

confidence: 99%

“…. The importance of paracrine signaling in driving disease manifestation in lymphatic anomalies is underscored by the finding that VEGF-C-driven growth of normal LECs into the bone is sufficient to recapitulate key aspects of disease pathology, including osteolysis, , which is characterized by cystic destruction of the lungs, core LAM cells carrying inactivating mutations in TSC1 or TSC2 express high levels of the other VEGFR3 ligand, VEGF-D, and thereby recruit a coating by normal LECs that induce cysts in the lungs98,99 .Direct cell-cell interaction between mutant and normal LECs may induce a phenotypic change in the latter and thereby promote their participation in the lesions. Interestingly, mosaic inactivation of VEGFR3 in LECs in mice promoted lymphatic vessel hyperplasia by activating proliferation of neighboring wild type LECs through cell-cell contact mediated regulation of NOTCH signaling46 , thus revealing a 'non-cell-autonomous' (i.e.…”

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confidence: 99%

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Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies

Mäkinen

Boon

Vikkula

et al. 2021

Circulation Research

118

133

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Lymphatic vessels maintain tissue fluid homeostasis by returning to blood circulation interstitial fluid that has extravasated from the blood capillaries. They provide a trafficking route for cells of the immune system, thus critically contributing to immune surveillance. Developmental or functional defects in the lymphatic vessels, their obstruction or damage, lead to accumulation of fluid in tissues, resulting in lymphedema. Here we discuss developmental lymphatic anomalies called lymphatic malformations and complex lymphatic anomalies that manifest as localized or multifocal lesions of the lymphatic vasculature, respectively. They are rare diseases that are caused mostly by somatic mutations and can present with variable symptoms based upon the size and location of the lesions composed of fluid-filled cisterns or channels. Substantial progress has been made recently in understanding the molecular basis of their pathogenesis through the identification of their genetic causes, combined with the elucidation of the underlying mechanisms in animal disease models and patient-derived lymphatic endothelial cells. Most of the solitary somatic mutations that cause lymphatic malformations and complex lymphatic anomalies occur in genes that encode components of oncogenic growth factor signal transduction pathways. This has led to successful repurposing of some targeted cancer therapeutics to the treatment of lymphatic malformations and complex lymphatic anomalies. Apart from the mutations that act as lymphatic endothelial cell–autonomous drivers of these anomalies, current evidence points to superimposed paracrine mechanisms that critically contribute to disease pathogenesis and thus provide additional targets for therapeutic intervention. Here, we review these advances and discuss new treatment strategies that are based on the recently identified molecular pathways.

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Needle in the Haystack: Finding the Elusive Lymphangioleiomyomatosis Cell

Cited by 2 publications

References 15 publications

mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline

mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline

Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies

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