Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

Dimitra Georgopoulou,H Raza Ali,Martin O’Reilly,Suet-Feung Chin,A Dariush,Sabina Cosulich ,Violeta Serra,Dario Bressan,Elham Esmaeilishirazifard,Alistair Martin,Larissa S Carnevalli,Abigail Shea,Gordon B Mills,Giulia Lerda,Fatime Qosaj,Maurizio Callari,Oscar M Rueda,Wendy Greenwood,Gregory J Hannon,Agnese Giovannetti,Alejandra Bruna,Elena Provenzano,Carlos Caldas

doi:10.1038/s41467-021-22303-z

Abstract

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

Highlights

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level
We have significantly extended this work by characterising the single-cell phenotypes of patient-derived tumour xenografts and correlating these with the genomic and transcriptomic profiles of these models, where we tested drug responses to compounds either used currently to routinely treat patients or under clinical development
We demonstrate the cellular phenotypic ‘footprints’ derived from mass cytometry form a distinctive feature that is not fully captured by genomic or transcriptomic stratification and constitute improved predictive biomarkers of drug response and resistance

Summary

Introduction

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Mass cytometry has been used to characterise breast cancer at the single-cell level in suspension[28] and in intact tumour tissue[29,31,32] These studies first highlighted the cellular phenotypic heterogeneity of human breast cancer and showed how this correlates with its genomic and transcriptomic landscapes. Significant limitations of these studies included not mapping cellular phenotypes to signalling states and not testing their value as predictive biomarkers for therapy response or resistance. We defined spatial architectures of cell phenotypes in imaging mass cytometry (IMC) data from both xenograft models and a cohort of human primary tumours[29], corroborating the validity of PDTXs as in vivo models of human disease and providing a roadmap toward clinical translation

Methods

Results

Conclusion