3 years ago

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

A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer
Alexis Blanchet-Cohen, Dongmei Zuo, Timothée Revil, Kevin Petrecca, Jamil Asselah, Claudia L. Kleinman, Mark Basik, Leah Liu, Sarkis Meterissian, Jiannis Ragoussis, Paul Savage, Morag Park, Atilla Omeroglu, Marie-Christine Guiot, Sadiq M.I. Saleh, Dunarel Badescu, Valentina Munoz-Ramos, Yu-Chang Wang, Nicholas R. Bertos

Summary

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

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31447-X

DOI: 10.1016/j.celrep.2017.10.015

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