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About the Lab

Human fibrotic diseases, including idiopathic pulmonary fibrosis, systemic sclerosis, liver cirrhosis, progressive kidney disease and desmoplastic tumors, cost the healthcare system nearly $10 billion per year. The central mission of the Lagares Laboratory is to perform innovative and cutting-edge research to unravel the biological mechanisms that regulate tissue regeneration, fibrosis (scarring) and tumor growth and metastasis. We investigate the biology of fibrosis and cancer with an implicit mission to develop novel therapeutic strategies for the treatment of these lethal diseases. Our research seeks to revolutionize the treatment of fibrotic diseases and cancer by developing two novel classes of drugs known as “mechano-therapeutics” and “senolytics”. To achieve this goal, the Lagares Laboratory utilizes cutting edge molecular biology techniques, new bioengineering assays, genetic manipulation of mice, animal modeling of disease, and translational studies in humans. The Lagares Laboratory is a fertile training ground for the next generation of scientists and physician-scientists.

Research Projects

The Lagares Laboratory at Massachusetts General Hospital utilizes cutting-edge molecular biology techniques, new bioengineering assays, genetic manipulation of mice, animal modeling of tissue injury and fibrosis and translational studies in humans to understand the biology of fibrotic diseases and ultimately develop innovative anti-fibrotic therapies.

Mechanobiology of fibrotic diseases and cancer

Tissue stiffening has traditionally thought to simply be a consequence of fibrosis. We have recently shown that matrix stiffness is in fact a major driver of fibrosis progression, through mechano-activation of myofibroblasts. Our results suggest that there is a feed-forward loop between matrix stiffening and fibroblast activation that amplifies fibrosis progression, but the mechanisms of this amplification loop have yet to be determined. Understanding the cellular and molecular determinants of progressive matrix stiffening consequently may help to improve understanding of the pathogenesis of fibrotic diseases and cancer, and identify new targets for mechano-therapeutics.
We have demonstrated in a series of publications that targeting mechanotransduction pathways in activated myofibroblasts dramatically ameliorated organ fibrosis in mouse models. Our research projects focus on the role of mechanotransduction pathways, including integrin signaling, FAK, ROCK, YAP/TAZ and MRTF-A, in regulating fibroblast activation in fibrosis and cancer.

Selected Publications

Tschumperlin D and Lagares D*. Mechano-therapeutics: Targeting Mechanical Signaling in Fibrosis and Tumor Stroma. Pharmacology and Therapeutics (2020) PMID: 32437826

Haak AJ, Kostallari E, Sicard D, Nouraie SM, Li X, Zhang Y, Kass DJ, Lagares D, Tager AM, Varelas X, Shah VH, Tschumperlin DJ. Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis. Science Translational Medicine (2019) PMCID: PMC7066514

Santos A, Lagares D*. Matrix Stiffness: The Conductor of Fibrosis. Current Rheumatology Reviews (2018) PMID: 29349703

Liu F, Lagares D, Choi KM, Stopfer L, Marinković A, Vrbanac V, Probst CK, Hiemer SE, Sisson TH, Horowitz JC, Rosas IO, Fredenburgh LE, Feghali-Bostwick C, Varelas X, Tager AM, Tschumperlin DJ. Mechanosignaling through YAP and TAZ drive fibroblast activation and fibrosis. Am J Physiol Lung Cell Mol Physiol (2015) PMCID: PMC4329470

Lagares D, Busnadiego O, García-Fernández RA, Kapoor M, Liu S, Carter D, Abraham D, Shi-Wen X, Carreira P, Fontaine B, Shea BS, Tager AM, Leask* A, Lamas S* and Rodríguez-Pascual F*. Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation. Arthritis Rheumatism (2012) PMCID: PMC3338902

Targeted apoptosis of senescent myofibroblasts to reverse established fibrosis

Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis. Our lab has recently demonstrated that a subset of myofibroblasts characterized by a pro-inflammatory senescence phenotype can be specifically targeted for apoptosis due to their increased mitochondrial priming (proximity to the apoptotic threshold). These “primed for death” senescent myofibroblasts appeared to be “addicted” to the anti-apoptotic protein BCL-XL to ensure survival. In preclinical studies, we have demonstrated that selective pharmacological inhibition of BCL-XL with the BH3 mimetic ABT-263 (also known as navitoclax) reverses established skin and lung fibrosis by inducing senescent myofibroblast apoptosis. In humans, dermal fibroblasts derived from patients with scleroderma (an autoimmune fibrotic disease) are similarly primed for death and more sensitive to ABT-263-induced apoptosis than control fibroblasts. Our findings demonstrate the potential efficacy of targeting myofibroblast anti-apoptotic proteins with BH3 mimetic senolytic drugs in scleroderma and other fibrotic diseases.

Selected Publications

Yan Zhou & David Lagares*. Anti-aging therapy for pulmonary fibrosis. Nature Aging (2021) 1, 155–156 https://doi.org/10.1038/s43587-021-00035-5

Hinz B and Lagares D*. Evasion of apoptosis by myofibroblasts: a hallmark of fibrotic diseases. Nature Reviews Rheumatology (2020) PMID: 31792399

Merkt W, Bueno M, Mora AL, Lagares D* Senotherapeutics: Targeting Senescence in Idiopathic Pulmonary Fibrosis. Semin Cell Biol. (2019) PMID: 31879264

Lagares D*, Fei L, Grasberger P, Probst CK, Sakai N, Ryan J, Bhola P, Montero J, Kapoor M, Baron M, Tschumperlin DJ, Letai A and Tager AM. Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-253 reverses established fibrosis. Science Translational Medicine. December 2017. PMID: 29237758

The ADAM10-sEphrin-B2 pathway in lung fibrosis and desmoplastic tumors

The identification of the molecular mediators directing activation of scar-forming myofibroblasts in organ fibrosis and cancer may provide novel targets for anti-fibrotic therapy. We have recently identified soluble ephrin-B2 (sEphrin-B2) as a new profibrotic mediator in lung fibrosis. Using mouse models of lung injury and fibrosis, we have demonstrated that the ectodomain of membrane-bound ephrin-B2 is shed by ADAM10 into the alveolar airspace following lung injury. Once shed, sEphrin-B2 is sufficient to drive myofibroblast formation and fibrosis. In genetic studies, we have demonstrated that mice lacking ephrin-B2 in fibroblasts exhibit marked protection from lung fibrosis. In humans, ADAM10/sEphrin-B2 signaling is upregulated in fibroblasts from patients with idiopathic pulmonary fibrosis, a fatal age-related fibrotic lung disease. Our studies identify sEphrin-B2, its receptors EphB3 and EphB4 and ADAM10 as novel therapeutic targets in lung fibrotic diseases. More recently, we have collaborated in a project validating the role of this pathway in the development of tumor fibrosis in pancreatic cancer.

Selected Publications

Lagares D*, Ghassemi-Kakaroodi P, Tremblay C, Santos DM, Grasberger P, Ahluwalia N, Probst CK, Montesi SB, Shea BS, Black KE, Knipe R, Blati M, Wu B, Baron M, Fahmi H, Gandhi R, Pardo A, Selman M, Wu J, Pelletier JP, Martel-Pelletier J, Tager AM and Kapoor K*. ADAM10-mediated ephrin-B2 shedding drives myofibroblast activation and tissue fibrosis. Nature Medicine (2017) PMID: 29058717

Wu B, Rockel JS, Lagares D* & Kapoor M*. Ephrins and Eph Receptor Signaling in Tissue Repair and Fibrosis. Current Rheumatology Reviews. March (2019). PMCID: PMC7112176

Mueller AC, Piper M, Goodspeed A, Galvao Neto A, Lagares D, Hansen KC, Van Bokhoven A, Karam SD. Induction of ADAM10 by RT drives fibrosis, resistance, and EMT in pancreatic cancer. Cancer Research (2021) PMID: 33526513


 

Lab Members

Principal Investigator

David Lagares, PhD

David Lagares, PhD
Assistant Professor of Medicine at Harvard Medical School
Director, Matrix and Mechanobiology Program, MGH Fibrosis Research Center
Principal Investigator at the Division of Pulmonary Critical Care Medicine and Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital
Co-Founder Mediar Therapeutics and Zenon Biotech

Research Group Members

Taslim Al-Hilal, PhD
Wolfgang Merkt, MD
Reza Roozafzoon, PhD
Poulami Datta, PhD
Hongwei Han, PhD
Yan Zhou, MSc
Maria-Anna Chrysorveri, BSc
Rachel Lister, BSc

Alumni

Tobias Kuehl, PhD
Alba Santos, PhD
Paula Grasberger, BSc
Clemens K Probst, BSc

Research Positions

If you are interested in applying for a postdoctoral position, or are a Harvard PhD student interested in a laboratory rotation, please e-mail your CV and a list of reference to Dr. David Lagares (dlagares@mgh.harvard.edu).

Publications

Click here to view publications from this investigator.