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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.

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. [ABSTRACT FROM AUTHOR]

C4.4A is a metastasis‐associated molecule that functions appear to rely on associated alph6beta4 integrin. To corroborate the impact of the C4.4A‐alpha6beta4 integrin association on metastasis formation, C4.4A was knocked‐down in a highly metastatic rat pancreatic adenocarcinoma (ASML, ASML‐C4.4Akd). Metastasis formation by ASML‐C4.4Akd cells after intrafootpad application was strongly retarded in draining nodes and lung colonization was rare. Furthermore, cisplatin treatment significantly prolonged the survival time only of ASML‐C4.4Akd‐bearing rats. ASML‐C4.4Akd cells display reduced migratory activity and impaired matrix protein degradation due to inefficient MMP14 activation; loss of drug‐resistance is due to mitigated PI3K/Akt pathway activation. These losses of function rely on the laminin receptor C4.4A recruiting activated alpha6beta4 integrin into rafts, where C4.4A cooperates with alpha6beta4 and via alpha6beta4 with MMP14. Within this raft‐located complex, MMP14 provokes focalized matrix degradation and mostly alpha6beta4 integrin promotes BAD phosphorylation and upregulated Bcl2 and BclXl expression. Thus, metastasis‐promoting activities of C4.4A are not genuine characteristics of C4.4A. Instead, the raft‐located laminin receptor C4.4A recruits alpha6beta4 integrin and supports via the alpha6beta4 integrin MMP14 activation. Thereby C4.4A acts as a linker to facilitate several steps in the metastatic cascade. Taking the restricted C4.4A expression in non‐transformed tissue, this knowledge should pave the way toward the use of C4.4A as a therapeutic target. Highlights: A knockdown of metastasis‐associated C4.4A impairs metastasis and drug resistance.Invasiveness and drug resistance are not genuine characteristics of C4.4A.The raft‐located laminin receptor C4.4A recruits alpha6beta4 and via alpha6beta4 MMP14.C4.4A‐associated alpha6beta4 initiates MMP14 activation provoking laminin degradation.Drug resistance by C4.4A‐associated alpha6beta4 relies on PI3K/AKT pathway activation. [ABSTRACT FROM AUTHOR]