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

Author:

Medina, Scott H

Bush, Brian

Cam, Maggie

Sevcik, Emily

DelRio, Frank W

Nandy, Kaustav

Schneider, Joel
Author Address

Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, 16802, United States. Electronic address: shm126@psu.edu., Materials Measurement Science Division, Nanomechanical Properties Group, National Institute of Standards and Technology, Gaithersburg, MD, 20899, United States., Office of Science and Technology Resources, Center for Cancer Research, National Institutes of Health, Bethesda, MD, 20892, United States., Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, United States., Applied Chemicals and Materials Division, Nanoscale Reliability Group, National Institute of Standards and Technology, Boulder, CO 80305, United States., Optical Microscopy and Analysis Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States., Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, United States. Electronic address: Joel.Schneider@nih.gov.,

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. Copyright © 2019. Published by Elsevier Ltd.

See More

Author Address