Solid tumors contain not only cancer cells, but also non-malignant cells such as fibroblasts, endothelial cells, and macrophages. In recently years, multiple lines of evidence have made it clear that these non- malignant cells, which together comprise the ?tumor microenvironment?, play crucial roles in disease progression and therapeutic response. Specifically, the activation of key signaling pathways in non-malignant cells of the microenvironment can render nearby tumor cells resistant to anticancer drugs. However, our understanding of the landscape of pathways that govern microenvironment-driven resistance is highly limited by the fact that no methods exist to perform large-scale pharmacological or genetic screening of the microenvironment. To address this challenge, we recently developed a microfluidics-based platform that enables the parallel co-culture of non-malignant and malignant cells in thousands of miniature, on-chip ?apartments?. In this proposal, we describe a strategy of systematically activating key signaling pathways in non-malignant cells using pooled lentiviral cDNA libraries, then assessing the impacts of these perturbations on drug sensitivity in nearby breast cancer cells. Specifically, we will use this strategy to map the microenvironmental signaling pathways that control the sensitivity of breast cancer cells to approved and emerging targeted therapies, then credential and validate hits from these assays using an integrated experimental and computational pipeline. Thus, this project will yield the first screening platform for large-scale functional dissection of cell-cell interactions and define key, clinically relevant microenvironmental pathways that shape anticancer drug responses.

Public Health Relevance

In recent years, it has become clear that the non-malignant cells that exist within a solid tumor can dramatically impact the sensitivity of nearby cancer cells to drug treatments. However, the mechanistic underpinnings of this interplay are largely unknown, as no experimental systems are compatible with large-scale functional dissection of tumor cell-microenvironment interactions. Here, we describe the construction of the first such system, which enables the functional credentialing of microenvironment-driven resistance at single cell resolution, along with its application to the problem of therapeutic resistance in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA220082-01A1
Application #
9526669
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Chen, Weiwei
Project Start
2018-02-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Ohiri, Korine A; Kelly, Sean T; Motschman, Jeffrey D et al. (2018) An acoustofluidic trap and transfer approach for organizing a high density single cell array. Lab Chip 18:2124-2133