Targeting cell durotaxis as a novel therapeutic strategy for idiopathic pulmonary fibrosis
Pneumology, Thoracic Surgery
Final Report Abstract
Idiopathic Pulmonary Fibrosis (IPF) is an incurable disease that leads to scarring of the lung. The scarring causes a progressive loss of lung function, which is, in most cases, fatal within a few years. Unfortunately, the two existing FDA-approved drugs only slow fibrosis progression without halting it. A better understanding of the mechanisms that cause and drive lung fibrosis is needed to identify novel and more effective therapies. Mechanobiology is a promising field of fibrosis research that focuses on how changes in the physical properties of the extracellular matrix (ECM), which makes up the scaffolding that permeates the lung, contribute to the disease. The main assumption is that increased stiffness of the ECM is not only the end result of scar formation and organ damage but is also part of an active feedback loop that promotes further fibrosis by influencing fibroblast behavior (cells producing collagen/other ECM proteins). Previous work has demonstrated that the increased stiffness of IPF lung tissue ECM is sufficient to cause myofibroblast differentiation. This means fibroblasts coming into contact with pathologically stiff ECM are converted to their active form, producing more collagen/ECM, hence worsening the disease. Interestingly, fibrotic lungs display a spatially heterogeneous stiffness profile with regions of high stiffness directly adjacent to regions with only slightly elevated or normal stiffness. Our hypothesis is that fibroblastic foci, accumulations of collagen and fibroblasts with focally increased stiffness, are crystallization points for a pro-fibrotic feed-forward cycle. An initial lung injury with dysregulated wound repair leads to increased stiffness, which attracts fibroblasts along a stiffness gradient via a process called durotaxis. These fibroblasts are then activated to produce more ECM, further increasing the stiffness of the tissue and thus further propagating the fibrotic process. Fibroblasts conduct mechanosensing, an assessment of the ECM stiffness around them, by connecting via a “molecular clutch.” Paxillin, an important part of this clutch, is instrumental in transducing information about the elevated stiffness into the fibroblast. We found that paxillin is necessary for fibroblasts to migrate towards areas of greater stiffness. In addition, we characterize which molecular changes of the paxillin molecule are responsible for this using a novel small molecule inhibitor that prevents fibroblast migration. Beyond this, we have found evidence that the enzyme ADAMTS14 is crucial in conveying the stiffness activation signal further into the nucleus, leading to fibroblast activation. In this context, we also found that modifications of microtubules, structurally important fibers that traverse fibroblasts, by the enzyme αTAT1 are important to fine-tune the mechanosensing response. Finally, we have advanced an imaging platform to, for the first time, observe durotaxis in a mammalian disease model in vivo.
Publications
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Conference contribution (poster) to the Annual Meeting of the American Thoracic Society (ATS) 2022; awarded with an abstract scholarship I. Ganzleben, M.-A. Chrysovergi, T.A. Al-Hilal, F. Liu, A. Santos, L.G. Vincent, C. Happe, E. Chaum, C.R. Yates, T.R. Mempel, A.J. Engler, D.J. Tschumperlin, and D. Lagares. Durotaxis in Lung Fibrosis: Transitioning from In Vitro Mechanisms to In Vivo Imaging (abstract). Am J Respir Crit Care Med 2022;205:A5551.
I. Ganzleben, M.-A. Chrysovergi, T.A. Al-Hilal, F. Liu, A. Santos, L.G. Vincent, C. Happe, E. Chaum, C.R. Yates, T.R. Mempel, A.J. Engler, D.J. Tschumperlin & D. Lagares
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Conference contribution (poster) to the Annual Meeting of the American Thoracic Society (ATS) 2024 A. Segal, I. Ganzleben, B. Ortiz Diaz, Y. Yang, D.V. Moutinho Dos Santos, L. Pantano, R.S. Knipe, G. Pronzati, K.E. Black, C. Godbout, P. Seither, F. Herrmann, and B.D. Medoff. Role of the Metallopeptidase ADAMTS14 in Mechanoactivation of Primary Human Lung Fibroblasts (abstract). Am J Respir Crit Care Med 2024;209:A2480.
A. Segal, I. Ganzleben, B. Ortiz Diaz, Y. Yang, D.V. Moutinho Dos Santos, L. Pantano, R.S. Knipe, G. Pronzati, K.E. Black, C. Godbout, P. Seither, F. Herrmann & B.D. Medoff
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Conference contribution (poster) to the Thomas L. Petty Aspen Lung Conference 2024 I. Ganzleben, A. Segal, D. Chow Ming Chia, S.-H. Yun, B. D. Medoff. Role of αTAT1 in the mechanobiology of lung fibrosis
I. Ganzleben, A. Segal, D. Chow Ming Chia, S.-H. Yun & B. D. Medoff
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Mechanobiology and the extracellular matrix in pulmonary fibrosis. IScience, 28(12), 113993
Ganzleben, Ingo & Medoff, Benjamin D.
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Spatial transcriptomics reveals altered communities and drivers of aberrant epithelia and pro-fibrotic fibroblasts in interstitial lung diseases. Cell Genomics, 6(3), 101066.
Jaiswal, Alok; Kooistra, Tristan; Pokatayev, Vladislav; Bastos, Hélder N.; Santos, Rita F.; Sarraf, Tresa R.; Segerstolpe, Åsa; Lin, Crystal; Amir-Zilberstein, Liat; Twardus, Shaina; Shannon, Kevin; Murphy, Shane P.; Knipe, Rachel; Ganzleben, Ingo K.; Black, Katharine E.; Delorey, Toni M.; Graham, Daniel B.; Hung, Yin P.; Hariri, Lida P.; Deguine, Jacques; Carvalho, Agostinho; Medoff, Benjamin D. & Xavier, Ramnik J.
