Multicellular contractility contributes to the emergence of mesothelioma nodules

Our plain-English summary of Multicellular contractility contributes to the emergence of mesothelioma nodules, by J. Tarnoki-Zach, P. Stockhammer, D.G. Isai, et al (Scientific Reports, 2020).

The study

• Authors: J. Tarnoki-Zach, P. Stockhammer, D.G. Isai, E. Mehes, B. Szeder, I. Kovacs, E. Bugyik, S. Paku, W. Berger, S.M. Thomas, Z. Neufeld, B. Dome, B. Hegedus, A. Czirok
• Journal: Scientific Reports
• Published: 2020;10(1):20114
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) has an overall poor prognosis and unsatisfactory treatment options. MPM nodules, protruding into the pleural cavity may have growth and spreading dynamics distinct that of other solid tumors. We demonstrate that multicellular aggregates can develop spontaneously in the majority of tested MPM cell lines when cultured at high cell density. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Prominent actin cables, spanning several cells, are abundant both in cultured aggregates and in MPM surgical specimens. We propose a computational model for in vitro MPM nodule development. Such a self-tensioned Maxwell fluid exhibits a pattern-forming instability that was studied by analytical tools and computer simulations. Altogether, our findings may underline a rational for targeting the actomyosin system in MPM.

In plain English

This laboratory study examined malignant pleural mesothelioma (MPM) cells using cell cultures, tumors grown in mice, surgical tissue from patients and computer simulations. It did not study asbestos. The authors grew MPM cell lines at high density and filmed them over many days. Around half of the cell lines established from MPM patients formed nodules, compared with 20% of tumor cell lines of epithelial origin. Non-malignant mesothelial cells stayed in a flat single layer. Nodules still formed when cell division was blocked with hydroxyurea. Two drugs that block the cells' contraction machinery, Y27632 and blebbistatin, reduced or prevented nodule formation. Y27632 cut measured contractility by 50% in SPC111 cultures and by 40% in VMC20 cultures. Long protein cables (actin cables) spanning several cells were seen in cultured nodules, in mouse tumors and in patient surgical specimens. A computer model of a contracting cell sheet produced similar patterns. The authors concluded that MPM cells can form nodules through cell contraction in vitro, which may support targeting this system. They noted that nodule formation was not specific to MPM and needs further study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: long-term live imaging of cultured cell lines, drug-inhibition experiments, a mouse xenograft model, staining of human surgical specimens, and computer simulations
• Who was studied: A panel of human MPM cell lines (for example SPC111, VMC20, P31cis, Meso53, Meso62, Meso80), non-MPM tumor cell lines, non-malignant primary mesothelial cells, SCID mice given SPC111 cells in the chest cavity, and frozen MPM tumor sections from the Biobank of the Department of Thoracic Surgery, Medical University of Vienna
• Exposure: No asbestos or fiber exposure was studied. The experimental treatments were the ROCK inhibitor Y27632 (50-100 µM), blebbistatin (40-80 µM), and hydroxyurea to block cell proliferation.
• Main results:
  • About half of the cell lines established from MPM patients formed macroscopic nodules in long-term high-density culture.
  • Similar nodules formed less often (20%) in tumor cell lines of epithelial origin.
  • Human non-malignant primary mesothelial cells stayed in a single layer, up to 17 days in culture (n = 2).
  • Among the MPM cell lines, nodule formation was not significantly associated with histological subtype or with major molecular alterations (BAP1, TP53, NF2 or TERT promoter mutations).
  • Nodules formed in SPC111 cultures even when proliferation was arrested with hydroxyurea.
  • Y27632 and blebbistatin substantially reduced or abolished stress cables and nodule formation. Previously formed nodules reversibly flattened when exposed to either drug.
  • Y27632 reduced contractility by 50% in SPC111 cultures and by 40% in VMC20 cultures.
  • Stress cables spanning multiple cells were also found in human MPM surgical specimens and in mouse xenograft tumors.
  • VMC20 nodules grown on collagen gels containing fluorescent beads took the beads into the body of the nodule.
  • Computer simulations of a contracting cell layer produced pattern formation similar to cultured MPM cells.
• The authors' conclusion: The authors concluded that MPM cells can form multicellular nodules through cell contractility-derived forces in vitro. They wrote that the ability of myosin-II inhibitors to disperse MPM nodules may support targeting actomyosin contractility in MPM.
• Limitations the authors state:
  • Nodule formation in vitro was more characteristic of MPM but neither specific nor exclusive to it; some non-MPM tumor cell lines also formed nodules.
  • Further work is needed to clarify the growth dynamics of in vitro nodule formation, and translational studies are needed.
  • The drug concentrations used were higher than those reported as effective in non-tumorous cells; the authors chose them for their 3D model.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Prognosis, Pleural Cavity.

Related studies

• Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow — I. Kovacs, E. Bugyik, et al. (2022)
• The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma — V. Laszlo, Z. Valko, et al. (2019)
• Restored expression of the MYO18B gene suppresses orthotopic growth and the production of bloody pleural effusion by human malignant pleural mesothelioma cells in SCID mice — N. Edakuni, K. Ikuta, et al. (2006)
• Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin — E. Giovannetti, P.A. Zucali, et al. (2011)
• The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice — T.T. Van, M. Hanibuchi, et al. (2011)
• Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression — D. Barbone, P. Cheung, et al. (2012)

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