MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness

Author:

Gonzalez‐Molina Jordi12ORCID,Hahn Paula1ORCID,Falcão Raul Maia34,Gultekin Okan1ORCID,Kokaraki Georgia23,Zanfagnin Valentina3,Braz Petta Tirzah34,Lehti Kaisa15ORCID,Carlson Joseph W.23ORCID

Affiliation:

1. Department of Microbiology, Tumor and Cell Biology Karolinska Institutet Stockholm Sweden

2. Department of Oncology‐Pathology Karolinska Institutet Stockholm 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

5. Department of Biomedical Laboratory Science Norwegian University of Science and Technology Trondheim Norway

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.

Funder

Barncancerfonden

Cancerfonden

Kreftforeningen

Vetenskapsrådet

Publisher

Wiley

Subject

Cancer Research,Genetics,Molecular Medicine,General Medicine,Oncology

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