Identification of a mechanogenetic link between substrate stiffness and chemotherapeutic response in breast cancer

Published

February 25, 2019

Author(s)

Brian G. Bush, Scott H. Medina, Emily Sevcik, Maggie Cam, Frank W. DelRio, Kaustav Nandy, Joel P. Schneider

Abstract

Mechanical feedback from the tumor microenvironment regulates an array of processes underlying cancer biology. For example, increased stiffness of mammary extracellular matrix (ECM) drives malignancy and alters the phenotypes of breast cancer cells. Despite this link, the role of substrate stiffness in chemotherapeutic response in breast cancer remains unclear. This is complicated by routine culture and adaptation of cancer cell lines to unnaturally rigid plastic or glass substrates, leading to profound changes in their growth, metastatic potential and, as we show here, chemotherapeutic response. We demonstrate that primary breast cancer cells undergo dramatic phenotypic changes when removed from the host microenvironment and cultured on rigid surfaces, and that drug responses are profoundly altered by the mechanical feedback cells receive from the culture substrate. Conversely, primary breast cancer cells cultured on substrates mimicking the mechanics of their host tumor ECM have a similar genetic profile to the in situ cells with respect to drug activity and resistance pathways. These results suggest substrate stiffness plays a significant role in susceptibility of breast cancer to clinically-approved chemotherapeutics, and presents an opportunity to improve drug discovery efforts by integrating mechanical rigidity as a parameter in screening campaigns.

Citation

Biomaterials

Volume

202

Pub Type

Journals

Download Paper

https://doi.org/10.1016/j.biomaterials.2019.02.018

Keywords

Chemotherapeutic drug screening, tumor rigidity, mechanical typing, breast cancer

Citation

Bush, B. , Medina, S. , Sevcik, E. , Cam, M. , DelRio, F. , Nandy, K. and Schneider, J. (2019), Identification of a mechanogenetic link between substrate stiffness and chemotherapeutic response in breast cancer, Biomaterials, [online], https://doi.org/10.1016/j.biomaterials.2019.02.018 (Accessed December 1, 2024)