LAM Cells as Potential Drivers of Senescence in Lymphangioleiomyomatosis Microenvironment

Bernardelli, Clara; Ancona, Silvia; Lazzari, Melania; Lettieri, Antonella; Selvaggio, Piera; Massa, Valentina; Gervasini, Cristina; Marco, Fabiano Di; Chiaramonte, Raffaella; Lesma, Elena

doi:10.3390/ijms23137040

Cited by 4 publications

(5 citation statements)

References 41 publications

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“…How TSC cysts prime their microenvironment to encourage and support growth is an emerging area. In the lung setting, TSC/LAM cells have been shown to induce senescence in neighbouring cells in a paracrine manner (Bernardelli et al., 2022 ). In a TSC renal cyst mouse model and TSC neural mouse model, wild‐type cells of the microenvironment were observed to take on an EV‐mediated Tsc2 ‐mutant disease phenotype (Kumar et al., 2021 ; Patel et al., 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Bhaoighill

Falcón‐Pérez

Royo

et al. 2023

J of Extracellular Vesicle

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Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2‐deficient and TSC2‐expressing cells and identified a distinct protein cargo in TSC2‐deficient EVs, containing an enrichment of proteins thought to be involved in tumour‐supporting signalling pathways. We show EVs from TSC2‐deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV‐associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.

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Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Bhaoighill

Falcón‐Pérez

Royo

et al. 2023

J of Extracellular Vesicle

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“…As demonstrated in other respiratory disease such as IPF, senescence might drive the progressive loss of parenchymal structure in LAM which ultimately causes the impairment of lung function ( 51 ). It has been demonstrated that LAM cells secrete molecules known to be SASP components comprised metalloproteinases ( 52 ), proinflammatory cytokines IL-6 ( 53 ) and IL-8 ( 50 ), kathepsin K ( 54 ), and VEGF-D ( 39 ) reinforcing the hypothesis of a LAM cell communication with the microenvironment and a SASP modulation of the remodeling of the lung parenchyma. Interestingly, IL-8, a potent neutrophil chemotactic factor that triggers chemotaxis and neutrophil activation through a phosphorylation cascade in the inflammatory response ( 55 ), has been demonstrated to be involved in the pathogenesis and progression of lung diseases such as ARDS and SARS CoV-2, suggesting the possibility to use IL-8 as a biomarker or as a therapeutic target ( 56 ).…”

Section: Lam and Mtormentioning

confidence: 90%

“…We recently demonstrated that LAM/TSC cells, derived by chylous thorax of a LAM/TSC patient, have senescent features dependent from mTOR hyperactivation and the capability to induce senescence in neighboring cells ( 50 ). As demonstrated in other respiratory disease such as IPF, senescence might drive the progressive loss of parenchymal structure in LAM which ultimately causes the impairment of lung function ( 51 ).…”

Section: Lam and Mtormentioning

confidence: 99%

Dysregulated lipid metabolism in lymphangioleiomyomatosis pathogenesis as a paradigm of chronic lung diseases

2023

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A chronic inflammatory condition characterizes various lung diseases. Interestingly, a great contribution to inflammation is made by altered lipids metabolism, that can be caused by the deregulation of the mammalian target of rapamycin complex-1 (mTORC1) activity. There is evidence that one of mTOR downstream effectors, the sterol regulatory element-binding protein (SREBP), regulates the transcription of enzymes involved in the de novo fatty acid synthesis. Given its central role in cell metabolism, mTOR is involved in several biological processes. Among those, mTOR is a driver of senescence, a process that might contribute to the establishment of chronic lung disease because the characteristic irreversible inhibition of cell proliferation, associated to the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP) supports the loss of lung parenchyma. The deregulation of mTORC1 is a hallmark of lymphangioleiomyomatosis (LAM), a rare pulmonary disease predominantly affecting women which causes cystic remodeling of the lung and progressive loss of lung function. LAM cells have senescent features and secrete SASP components, such as growth factors and pro-inflammatory molecules, like cancer cells. Using LAM as a paradigm of chronic and metastatic lung disease, here we review the published data that point out the role of dysregulated lipid metabolism in LAM pathogenesis. We will discuss lipids’ role in the development and progression of the disease, to hypothesize novel LAM biomarkers and to propose the pharmacological regulation of lipids metabolism as an innovative approach for the treatment of the disease.

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“…In all the experiments, TSC2 -/meth cells were cultured for 3 up to 5 passages (meaning for about 20 days after the thawing), as we previously described [ 22 ]. This precaution allowed us to maintain and standardize the primary features of these cells.…”

Section: Methodsmentioning

confidence: 99%

Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model

Bernardelli

Chiaramonte

Ancona

et al. 2022

IJMS

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Cutaneous lesions are one of the hallmarks of tuberous sclerosis complex (TSC), a genetic disease in which mTOR is hyperactivated due to the lack of hamartin or tuberin. To date, novel pharmacological treatments for TSC cutaneous lesions that are benign but still have an impact on a patient’s life are needed, because neither surgery nor rapamycin administration prevents their recurrence. Here, we demonstrated that primary TSC2-/meth cells that do not express tuberin for an epigenetic event caused cutaneous lesions and follicular neogenesis when they were subcutaneously injected in nude mice. Tuberin-null cells localized in the hair bulbs and alongside mature hairs, where high phosphorylation of S6 and Erk indicated mTOR hyperactivation. Interestingly, 5-azacytidine treatment reduced hair follicles, indicating that chromatin remodeling agents might be effective on TSC lesions in which cells lack tuberin for an epigenetic event. Moreover, we demonstrated that the primary TSC2-/meth cells had metastatic capability: when subcutaneously injected, they reached the bloodstream and lymphatics and invaded the lungs, causing the enlargement of the alveolar walls. The capability of TSC2-/meth cells to survive and migrate in vivo makes our mouse model ideal to follow the progression of the disease and test potential pharmacological treatments in a time-dependent manner.

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LAM Cells as Potential Drivers of Senescence in Lymphangioleiomyomatosis Microenvironment

Cited by 4 publications

References 41 publications

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Dysregulated lipid metabolism in lymphangioleiomyomatosis pathogenesis as a paradigm of chronic lung diseases

Primary TSC2-/meth Cells Induce Follicular Neogenesis in an Innovative TSC Mouse Model

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