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Using Microarrays to Interrogate Microenvironmental Impact on Cellular Phenotypes in Cancer
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Using Microarrays to Interrogate Microenvironmental Impact on Cellular Phenotypes in Cancer

Published on: May 21, 2019

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

Chun-Han Lin1, Tiina Jokela2, Joe Gray3

  • 1Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

Cell Reports
|October 12, 2017
PubMed

Insights

Tumor microenvironments significantly impact anti-cancer drug effectiveness. Researchers identified specific microenvironment components that drive resistance to lapatinib, offering new strategies to improve cancer therapy efficacy.

Area of Science:

  • Oncology
  • Biomaterials Science
  • Cell Biology

Background:

  • Tumor microenvironments (TMEs) are critical regulators of anti-cancer drug resistance.
  • Understanding complex cell-microenvironment interactions is challenging but essential for therapeutic development.

Purpose of the Study:

  • To systematically assess the impact of diverse tumor-inspired microenvironments on lapatinib response in cancer cells.
  • To identify specific extracellular matrix (ECM) and soluble factors that modulate drug sensitivity and resistance.

Main Methods:

  • Generation of hundreds of controlled microenvironments using stiffness-tunable substrata printed with ECM and soluble factors.
  • High-content single-cell analysis of proliferation, HER2 protein expression/phosphorylation, and cell morphology.
  • Application of dimension reduction and linear modeling to identify key microenvironment regulators, followed by empirical validation.

Main Results:

  • Each cancer cell line exhibited unique patterns of response to varying microenvironments.
  • Fibronectin, type IV collagen, and matrix rigidity were identified as significant drivers of lapatinib resistance in HER2-amplified breast cancer cells.
  • Small-molecule inhibitors capable of overcoming microenvironment-imposed resistance were discovered.

Conclusions:

  • A high-throughput strategy can effectively dissect microenvironment contributions to drug resistance.
  • Identifying resistance-driving microenvironments is crucial for developing more effective anti-cancer therapeutics.
  • Targeting specific microenvironment components or using combination therapies can overcome drug resistance.
Keywords:
AZD0530HER2MEMAYAPbreast cancerdrug resistancefibronectinlapatinibmicroenvironmentmicroenvironment microarrayverteporfin

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