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Matrix topography induces a cytoskeletal and transcriptional memory supporting metastasis

ABSTRACT: The extracellular matrix (ECM) is a crucial component of solid tumours. Using digital pathology in human and mouse tissues, we define 3 matrix regions: the tumour body (TB), the proximal invasive front (PIF)- and a further distal invasive front (DIF) Increased matrix density coupled to larger fibre thickness, length and alignment are all features of both invasive areas. Importantly, radial fibre orientation is a characteristic of the distal invasive front. Using several in vivo and in vitro 3-dimensional (3D) models, we show that matrix density and alignment induces RhoA/C-ROCK-Myosin activity in cancer cells, while maximal amoeboid directed migration correlates with areas of radial fibre orientation. Importantly, matrix topographical features are enough to prime cancer cells for successful local invasion and metastatic colonisation. Using several spatial OMICs, we describe a mechano-inflammatory transcriptional program linked to matrix topographical features in the invasive fronts of primary tumours that is preserved in metastatic lesions and strongly linked to worse prognosis in patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE263097 | GEO | 2024/12/01

REPOSITORIES: GEO

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