Disentangling the fibrous microenvironment: designer culture models for improved drug discovery

ABSTRACT

Introduction

Standard high-throughput screening (HTS) assays rarely identify clinically viable ‘hits’, likely because cells do not experience physiologically realistic culture conditions. The biophysical nature of the extracellular matrix has emerged as a critical driver of cell function and response and recreating these factors could be critically important in streamlining the drug discovery pipeline.

Areas covered

The authors review recent design strategies to understand and manipulate biophysical features of three-dimensional fibrous tissues. The effects of architectural parameters of the extracellular matrix and their resulting mechanical behaviors are deconstructed; and their individual and combined impact on cell behavior is examined. The authors then illustrate the potential impact of these physical features on designing next-generation platforms to identify drugs effective against breast cancer.

Expert opinion

Progression toward increased culture complexity must be balanced against the demanding technical requirements for high-throughput screening; and strategies to identify the minimal set of microenvironmental parameters needed to recreate disease-relevant responses must be specifically tailored to the disease stage and organ system being studied. Although challenging, this can be achieved through integrative and multidisciplinary technologies that span microfabrication, cell biology, and tissue engineering.

KEYWORDS:

• High throughput screening (HTS)
• microenvironment
• biophysics
• mechanobiology
• breast cancer
• culture models
• tissue engineering

Article highlights

• Biophysical features of the extracellular matrix have emerged as critically important regulators of cellular function, but the increased complexity of these systems provides considerable challenges in designing next-generation HTS platforms.

• Identifying a minimal set of biophysical features needed to prompt realistic cellular activity is essential, but is likely to be disease- and tissue-specific.

• Tissue architecture and mechanical behaviors are intimately linked, and critically important for cell function; and their individual contributions can be identified using well defined in vitro culture technologies.

• Cellular structures, fiber microstructure and organization; and biomechanical parameters including tissue stiffness, viscoelasticity, and plasticity are more complex than originally thought, and can have disease-specific effects on cell-response.

• These culture models have strong potential utility in designing next generation breast cancer screening platforms.

• To streamline the drug development pipeline, there is a need for fundamental disease-specific knowledge about the key microenvironmental drivers of cell function to emerge in parallel with novel technologies to recreate these features in HTS-compatible formats.

This box summarizes key points contained in the article.

Acknowldegement

The authors also gratefully acknowledge support from the NSERC Postgraduate Scholarships program to W Lee and N Kalashnikov, and the Canada Research Chairs in Advanced Cellular Microenvironments to C Moraes.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Canadian Cancer Society (Grants #704422, #706002), the Canadian Institutes of Health Research (Grant # 01871-000), and the Natural Sciences and Engineering Research Council of Canada (Discovery RGPIN-2015-05512).