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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalBiomaterials
Volume202
DOIs
StatePublished - May 1 2019

Fingerprint

Stiffness
Breast Neoplasms
Cells
Substrates
Cell culture
Extracellular Matrix
Tumors
Neoplasms
Feedback
Tumor Microenvironment
Drug Discovery
Mechanics
Drug Resistance
Rigidity
Pharmaceutical Preparations
Plastics
Glass
Cultured Cells
Screening
Breast

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Medina, Scott H. ; Bush, Brian ; Cam, Maggie ; Sevcik, Emily ; DelRio, Frank W. ; Nandy, Kaustav ; Schneider, Joel P. / Identification of a mechanogenetic link between substrate stiffness and chemotherapeutic response in breast cancer. In: Biomaterials. 2019 ; Vol. 202. pp. 1-11.
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Identification of a mechanogenetic link between substrate stiffness and chemotherapeutic response in breast cancer. / Medina, Scott H.; Bush, Brian; Cam, Maggie; Sevcik, Emily; DelRio, Frank W.; Nandy, Kaustav; Schneider, Joel P.

In: Biomaterials, Vol. 202, 01.05.2019, p. 1-11.

Research output: Contribution to journalArticle

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