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

Nat Commun. 2021 Mar 31;12(1):1998. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Heterografts / drug effects*
  • Heterografts / metabolism
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Morpholines / pharmacology*
  • Piperazines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology*
  • Pyrimidines / pharmacology*
  • Treatment Outcome
  • Xenograft Model Antitumor Assays / methods*

Substances

  • Benzamides
  • Morpholines
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrimidines
  • vistusertib
  • palbociclib