A single-cell atlas of breast cancer cell lines to study tumour heterogeneity and drug response

Breast Cancer (BC) patient stratification is mainly driven by tumour receptor status and histological grading and subtyping, with about twenty percent of patients for which absence of any actionable biomarkers results in no clear therapeutic intervention to apply. Here, we evaluated the potential of single-cell transcriptomics for automated diagnosis and drug treatment of breast cancer. We transcriptionally profiled 35,276 individual cells from 32 BC cell-lines covering all main BC subtypes to yield a Breast Cancer Single Cell Atlas. We show that single cell transcriptomics can successfully detect clinically relevant BC biomarkers and that atlas can be used to automatically predict cancer subtype and composition from a patient’s tumour biopsy. We found that BC cell lines harbour a high degree of heterogeneity in the expression of clinically relevant BC biomarkers and that such heterogeneity enables cells with differential drug sensitivity to co-exist even within a genomically stable isogenic cell line. Finally, we developed a novel bioinformatics approach named DREEP (Drug Response Estimation from Expression Profiles) to automatically predict responses to more than 450 anticancer agents starting from single-cell transcriptional profiles. We validated DREEP both in-silico and in-vitro by selectively inhibiting the growth of the HER2-deficient subpopulation in the MDAMB361 cell line. Our work shows that transcriptional heterogeneity is common, dynamic and that its plasticity plays a relevant role in determining drug sensitivity. Moreover, our Breast Cancer Single Cell Atlas and DREEP approach are a unique resource for the BC research community and to advance the use of single-cell sequencing in the clinic. Overall design: Single-cell sequencing of 32 breast cancer cell-lines

Downloaded and exported data is governed by the HCA Data Release Policy and licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). For more information please see our Data Use Agreement.