Matrix Mechanical Properties and the Invasive Potential of Metastatic Cancer

Abstract

Recent studies suggest that cancer cells undergo genotypic and phenotypic changes in response to the rigidity of the extracellular matrix (ECM). These studies have focused largely on non-mineralized tissues in the kPa range (corresponding to soft tissue), while many tissues important in the progression of cancer, such as mineralized bone (O(10⁹ Pa)) and the basement membrane (O(10⁶Pa)), far exceed those values. In this work, we employed the use of in vitro culture systems spanning the entire range of tissue elasticity (10³-10⁹ Pa) to study the invasive potential of breast cancer. Here, we demonstrate that cancer cells can sense a wide range of rigidities, and show increased ECM degradation by invadopodia in response to rigidity. Furthermore, we show that the rigidity of bone, a preferential target for breast cancer, specifically induces changes in parathyroid hormone related protein (PTHrP) and its transcription factor Gli2 in the cancer cell to facilitate degradation and invasion of the bone matrix. We find that these genotypic changes are mediated by mechanotransduction, as bone-like matrix rigidity induced clustering of β3 integrin and TGF-β receptor type II (TGF-βRII) to stimulate expression of PTHrP and Gli2 through Src, Rho-kinase (ROCK) and mitogen activated protein kinase (MAPK). These observations demonstrate the need for physiologically relevant in vitro culture systems and suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis. These findings could lead to new clinical targets for the treatment of bone metastases, a major contributor in the lethality of metastatic cancer, for which no effective therapies exist to date.