Cell Rep 2017 Oct;21(5):1140-1149
Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada; McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1A4, Canada; Center of Innovation in Personalized Medicine, Cancer and Mutagen Unit, King Fahd Center for Medical Research, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address:
Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer. Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR. Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster. Sorted EGFR subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFR cells gave rise to EGFR and EGFR cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFR subpopulations were identified in independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity. This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention.