A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

作者：Savage Paul; Blanchet Cohen Alexis; Revil Timothee; Badescu Dunarel; Saleh Sadiq M I; Wang Yu Chang; Zuo Dongmei; Liu Leah; Bertos Nicholas R; Munoz Ramos Valentina; Basik Mark; Petrecca Kevin; Asselah Jamil; Meterissian Sarkis; Guiot Marie Christine; Omeroglu Atilla; Kleinman Claudia L; Park Morag^*; Ragoussis Jiannis^*

来源：Cell Reports, 2017, 21(5): 1140-1149.

DOI：10.1016/j.celrep.2017.10.015

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(hi) subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential. EGFR(hi) cells gave rise to EGFR(hi) and EGFR(lo) cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition. Similar tumorigenic EGFR(hi) 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.

• 出版日期2017-10-31
• 单位McGill