Combinatorial Microenvironments Impose a Continuum of Cellular Responses to a Single Pathway-Targeted Anti-cancer Compound

Chun Han Lin, Tiina Jokela, Joe Gray, Mark A. LaBarge

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Tumor microenvironments are a driver of resistance to anti-cancer drugs. Dissecting cell-microenvironment interactions into tractable units of study presents a challenge. Here, we assess the impact of hundreds of tumor-inspired microenvironments, in parallel, on lapatinib responses in four cancer cell lines. Combinations of ECM and soluble factors were printed on stiffness-tunable substrata to generate a collection of controlled microenvironments in which to explore cell-based functional responses. Proliferation, HER2 protein expression and phosphorylation, and morphology were measured in single cells. Using dimension reduction and linear modeling, the effects of microenvironment constituents were identified and then validated empirically. Each of the cell lines exhibits unique microenvironment-response patterns. Fibronectin, type IV collagen, and matrix rigidity are significant regulators of lapatinib resistance in HER2-amplified breast cancer cells. Small-molecule inhibitors were identified that could attenuate microenvironment-imposed resistance. Thus, we demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments to improve the efficacy of anti-cancer therapeutics. Tumor microenvironments are a driver of anti-cancer drug resistance. Lin et al. use microenvironment microarrays and a cell-based functional approach to identify microenvironment components that modulate lapatinib responses in isogenic cells. They demonstrate a strategy to identify resistance- and sensitivity-driving microenvironments that may improve the understanding and efficacy of anti-cancer therapeutics.

Original languageEnglish (US)
Pages (from-to)533-545
Number of pages13
JournalCell Reports
Volume21
Issue number2
DOIs
StatePublished - Oct 10 2017

Keywords

  • AZD0530
  • HER2
  • MEMA
  • YAP
  • breast cancer
  • drug resistance
  • fibronectin
  • lapatinib
  • microenvironment
  • microenvironment microarray
  • verteporfin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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