Extracellular matrix stiffening promotes ovarian cancer progression by altering exosome secretion and contents

Extracellular matrix (ECM) stiffening plays a pivotal role in modulating the tumour microenvironment (TME) and thus promotes oncogenic transformation and cancer progression. Recent studies have underscored the correlations between ECM stiffening and the rates of tumour progression, invasive behaviour, and overall prognosis in patients with ovarian cancer. However, the specific mechanisms by which ECM stiffening influences the migratory and invasive behaviour of ovarian cancer cells remain elusive. In this study, we demonstrated that ECM stiffening in ovarian tumours not only promotes exosome secretion from tumour cells but also alters the protein composition and levels within these exosomes, thus impacting cell migration and invasion. Specifically, as the ECM stiffens, the proliferation of ovarian cancer cells increases significantly, accompanied by a marked increase in exosome secretion. Notably, ECM stiffening can change the levels of internal proteins such as p-mTOR, p-p70s6k, p-Akt (S473), p-4EBP1 (S65), and p-S6K (T389) and thus activate the Akt‒mTOR signalling pathway in ovarian cancer cells. Similarly, ECM stiffening also alters the levels of Jagged 1/2, Sox9, Hes1, and c-Myc and thus activates the Notch signalling pathway. Collectively, these findings demonstrate that ECM stiffening can significantly promote the proliferation, migration, and invasion of ovarian cancer cells, likely through the activation of both the Akt–mTOR and Notch signalling pathways.