Lymphangioleiomyomatosis (LAM) Cell Atlas

Du, Yina; Guo, Minzhe; Wu, Yixin; Wagner, Andrew J.; Perl, Anne‐Karina T.; Wikenheiser-Brokamp, Kathryn A.; Yu, Jane; Gupta, Nishant; Kopras, E.J.-A.; Krymskaya, Vera P.; Obraztsova, Kseniya; Tang, Yan; Kwiatkowski, David J.; Henske, Elizabeth P.; McCormack, Francis X.; Xu, Yan

doi:10.1136/thoraxjnl-2022-218772

Cited by 9 publications

(10 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To determine the presence of senescent cells in LAM lung tissue, we initially examined gene expression of two canonical senescence markers, the cyclin dependent kinase (CDK) inhibitors CDKN1A (p21) and CDKN2A (p16), using the LAM cell atlas, an open-source data interface comprising single cell RNA sequencing data from 13 lung samples 24 . p21 was ubiquitously expressed throughout the LAM lung including in TSC null LAM core cells.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Babaei-Jadidi,

Clements,

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Lymphangioleiomyomatosis (LAM) is a rare disease which causes lung cysts and respiratory failure. TSC2 deficient LAM cells with dysregulated mTOR signalling form nodules with fibroblasts causing lung injury. We examined if mTOR dysregulation could induce senescence and impair responses to lung injury. Senescence markers p21 and p16 were increased in LAM lungs and co-localised with alveolar type 2 cells. The SenMayo senescence gene panel was upregulated in LAM alveolar type 2 cells with senescence supressed by mTOR inhibition in patients. LAM cell / fibroblast spheroid cultures induced senescence markers in alveolar type 2 cell organoids, altered their growth and delayed epithelial scratch wound repair. Upstream regulator analysis predicted alveolar type 2 cell IL6 receptor activation. IL6 was produced by LAM cells, induced p16 and p21 in alveolar type 2 cells, inhibited epithelial wound resolution and was overexpressed in LAM patient serum where it was related to lung function. Wound repair in the presence of TSC2 null LAM cell / fibroblast spheroids was enhanced by the IL6 receptor antagonist Tocilizumab. Our findings show TSC2 loss induces senescence and IL6 production which are associated with impaired lung repair. Targeting IL6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.

show abstract

Section: Resultsmentioning

confidence: 99%

“…(A) Single cell RNA sequencing of LAM lung tissues showing expression of p16 and p21 in LAM lung populations using the LAM cell atlas 24 . Left panels show expression of positive cells for p21 and p16 in each cluster, right panels show the fold change and significance for LAM compared with control lung.…”

Section: Resultsmentioning

confidence: 99%

mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Babaei-Jadidi,

Clements,

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In sum, these studies suggest that both cells of uterine and lung mesenchyme origin may be involved in the development of LAM -perhaps the former comprise the core smooth muscle cell-like LAM tumor cells, while the latter are responsible for the cystic lung disease. More studies that include use of a newly developed LAM Cell Atlas (Du et al 2023) will help clarify these questions.…”

Section: Origin and Nature Of Lam Cellsmentioning

confidence: 99%

“…Characterization of the human LAM tumor immune microenvironment is nascent, and the myeloid content of LAM lesions is understudied. The LAM Cell Atlas (Du et al 2023) has identified various immune cell populations in the LAM lung, including tumor-perturbed neutrophils (Minor et al 2023), as well as inflammatory macrophage and monocyte populations, conventional and plasmacytoid dendritic cells, and other granulocytes such as mast cells and basophils. While a few studies have suggested a potential role for macrophages and monocytes in the immune-suppressive LAM tumor immune microenvironment, as mentioned above, only mast cells and neutrophils have been assessed by functional assay, leaving much to be illuminated about the significance of the diverse myeloid compartment of the LAM tumor immune microenvironment.…”

Section: The Immune Microenvironment and Lammentioning

confidence: 99%

Lymphangioleiomyomatosis: where endocrinology, immunology and tumor biology meet

Gibbons

Minor

Hammes

2023

Endocrine-Related Cancer

View full text Add to dashboard Cite

Lymphangioleiomyomatosis (LAM) is a cystic lung disease found almost exclusively in genetic females and caused by small clusters of smooth muscle cell tumors containing mutations in one of the two tuberous sclerosis genes (TSC1 or TSC2). Significant advances over the past 2-3 decades have allowed researchers and clinicians to more clearly understand the pathophysiology of LAM, and therefore better diagnose and treat patients with this disease. Despite substantial progress, only one proven treatment for LAM is used in practice: mTORC1 inhibition with medications such as sirolimus. While mTORC1 inhibition effectively slows LAM progression in many patients, it is not curative, is not effective in all patients, and can be associated with significant side effects. Furthermore, the presence of established and accurate biomarkers to follow LAM progression is limited. That said, discovering additional diagnostic and treatment options for LAM is paramount. This review will describe recent advances in LAM research, centering on the origin and nature of the LAM cell, the role of estrogen in LAM progression, the significance of melanocytic marker expression in LAM cells, and potential roles of the microenvironment in promoting LAM tumor growth. By appreciating these processes in more detail, researchers and caregivers may be afforded novel approaches to aid in the treatment of patients with LAM.

show abstract

“…A publicly available LAM cell atlas has been constructed using single-cell RNA sequencing LAM lung data from three research groups. This resource allows for convenient exploration of the transcriptome of the LAM lung ( https://research.cchmc.org/pbge/lunggens/LCA/LCA.html ) [ 8 ].…”

Section: Introduction To Lymphangioleiomyomatosismentioning

confidence: 99%

Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis

Evans,

McCormack,

Sonenberg

et al. 2023

Eur Respir Rev

View full text Add to dashboard Cite

Lymphangioleiomyomatosis (LAM) is a cystic lung disease of women resulting from mutations in tuberous sclerosis complex (TSC) genes that suppress the mammalian target of rapamycin complex 1 (mTORC1) pathway. mTORC1 activation enhances a plethora of anabolic cellular functions, mainlyviathe activation of mRNA translation through stimulation of ribosomal protein S6 kinase (S6K1)/ribosomal protein S6 (S6) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1)/eukaryotic translation initiation factor 4E (eIF4E). Rapamycin (sirolimus), an allosteric inhibitor of mTORC1, stabilises lung function in many but not all LAM patients and, upon cessation of the drug, disease progression resumes. At clinically tolerable concentrations, rapamycin potently inhibits the ribosomal S6K1/S6 translation ribosome biogenesis and elongation axis, but not the translation 4E-BP1/eIF4E initiation axis. In this mini-review, we propose that inhibition of mTORC1-driven translation initiation is an obvious but underappreciated therapeutic strategy in LAM, TSC and other mTORC1-driven diseases.

show abstract

Lymphangioleiomyomatosis (LAM) Cell Atlas

Cited by 9 publications

References 10 publications

mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

mTOR dysregulation induces IL6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis

Lymphangioleiomyomatosis: where endocrinology, immunology and tumor biology meet

Lost in translation: a neglected mTOR target for lymphangioleiomyomatosis

Contact Info

Product

Resources

About