Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning

Adam W. Watson, Adam D. Grant, Sara S. Parker, Samantha Hill, Michael B. Whalen, Jayati Chakrabarti, Michael W. Harman, Mackenzie R. Roman, Brittany L. Forte, Cody C. Gowan, Raúl Castro-Portuguez, Lindsey K. Stolze, Christian Franck, Darren A. Cusanovich, Yana Zavros, Megha Padi, Casey E. Romanoski, Ghassan Mouneimne

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

While the immediate and transitory response of breast cancer cells to pathological stiffness in their native microenvironment has been well explored, it remains unclear how stiffness-induced phenotypes are maintained over time after cancer cell dissemination in vivo. Here, we show that fibrotic-like matrix stiffness promotes distinct metastatic phenotypes in cancer cells, which are preserved after transition to softer microenvironments, such as bone marrow. Using differential gene expression analysis of stiffness-responsive breast cancer cells, we establish a multigenic score of mechanical conditioning (MeCo) and find that it is associated with bone metastasis in patients with breast cancer. The maintenance of mechanical conditioning is regulated by RUNX2, an osteogenic transcription factor, established driver of bone metastasis, and mitotic bookmarker that preserves chromatin accessibility at target gene loci. Using genetic and functional approaches, we demonstrate that mechanical conditioning maintenance can be simulated, repressed, or extended, with corresponding changes in bone metastatic potential.

Original languageEnglish (US)
Article number109293
JournalCell Reports
Volume35
Issue number13
DOIs
StatePublished - Jun 29 2021

Keywords

  • ATACseq
  • RUNX2
  • biomechanics
  • bone metastasis
  • breast cancer
  • matrix stiffness
  • mechanical memory
  • osteolysis
  • phenotypic plasticity
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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