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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.

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Edited by Tamas DalmayKeywords: Non-small cell lung cancer miR-152 ADAM metallopeptidase domain 17 Proliferation Migration Invasion a b s t r a c t MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been suggested to play an essential role in tumorigenesis. In this study, we show that miR-152 is significantly downregulated in non-small cell lung cancer (NSCLC) tissues and cell lines. Restoration of miR-152 significantly reduces proliferation, colony formation, migration and invasion of NSCLC cells. In addition, ADAM metallopeptidase domain 17 (ADAM17) is identified as a target of miR-152 in NSCLC cells, and miR-152-induced suppression of cell proliferation, colony formation, migration and invasion is partially mediated by silencing of ADAM17 expression. Furthermore, ADAM17 inversely correlates with miR-152 in NSCLC tissues. Collectively, our findings indicate that miR-152 acts as tumor suppressor in NSCLC partially via targeting ADAM17.