MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness

Area of Science:

• Oncology
• Biochemistry
• Biomaterials Science

Background:

• Fibrillar collagen, stiffness, and signaling promote benign uterine leiomyomas (LMs) and aggressive carcinomas.
• The role of fibrillar collagens in malignant mesenchymal tumors like uterine leiomyosarcoma (uLMS) is not well understood.
• Understanding collagen's role in uLMS is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the network morphology and density of fibrillar collagens in uLMS, LM, and normal myometrium (MM).
• To analyze gene expression related to collagen remodeling in these tissues.
• To explore the functional impact of collagen microenvironments on uLMS cell behavior.

Main Methods:

• Analysis of collagen network morphology and density in uLMS, LM, and MM tissues.
• Gene expression profiling focusing on collagen-remodeling enzymes.
• 3D matrix culture experiments to assess uLMS cell proliferation and migration on varying collagen stiffness.
• Investigation of the role of matrix metalloproteinase-14 (MMP14) and yes-associated protein 1 (YAP) signaling.

Main Results:

• uLMS tumors exhibit lower collagen density and increased expression of collagen-remodeling genes compared to LMs.
• MMP14, overexpressed in uLMS, promotes uLMS cell proliferation in collagen-based 3D matrices.
• uLMS cells show reduced sensitivity to substrate stiffness, with growth in soft matrices sustained by enhanced YAP activity.

Conclusions:

• uLMS cells possess enhanced collagen-remodeling capabilities, adapting to grow in soft, low-collagen environments.
• Matrix remodeling and YAP signaling represent potential therapeutic targets for uterine leiomyosarcoma.
• These findings offer new insights into the unique microenvironmental adaptations of malignant mesenchymal tumors.