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MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness.

Authors
  • Gonzalez-Molina, Jordi1, 2
  • Hahn, Paula1
  • Falcão, Raul Maia3, 4
  • Gultekin, Okan1
  • Kokaraki, Georgia2, 3
  • Zanfagnin, Valentina3
  • Braz Petta, Tirzah3, 4
  • Lehti, Kaisa1, 5
  • Carlson, Joseph W2, 3
  • 1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 2 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
  • 3 Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • 4 Department of Cellular Biology and Genetics, Federal University of Rio Grande do Norte, Natal, Brazil. , (Brazil)
  • 5 Department of Biomedical Laboratory Science, Norwegian University of Science and Technology, Trondheim, Norway. , (Norway)
Type
Published Article
Journal
Molecular Oncology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Apr 01, 2024
Volume
18
Issue
4
Pages
850–865
Identifiers
DOI: 10.1002/1878-0261.13440
PMID: 37078535
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Fibrillar collagen deposition, stiffness and downstream signalling support the development of leiomyomas (LMs), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared with epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (uLMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression within uLMS, LM and normal myometrium (MM). We find that, in contrast to LM, uLMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that matrix metalloproteinase-14 (MMP14), a central protein with collagen-remodelling functions that is particularly overexpressed in uLMS, supports uLMS cell proliferation. In addition, we find that, unlike MM and LM cells, uLMS proliferation and migration are less sensitive to changes in collagen substrate stiffness. We demonstrate that uLMS cell growth in low-stiffness substrates is sustained by an enhanced basal yes-associated protein 1 (YAP) activity. Altogether, our results indicate that uLMS cells acquire increased collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease. © 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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