Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma

Cell. 2022 Jan 20;185(2):299-310.e18. doi: 10.1016/j.cell.2021.12.023.

Abstract

Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.

Keywords: DCIS; MIBI; breast cancer; myoepithelium; spatial proteomics; systems biology; tumor microenvironment; tumor progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / pathology*
  • Carcinoma, Intraductal, Noninfiltrating / pathology
  • Cell Differentiation
  • Cohort Studies
  • Disease Progression
  • Epithelial Cells / pathology
  • Epithelium / pathology
  • Extracellular Matrix / metabolism
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local / pathology
  • Phenotype
  • Single-Cell Analysis
  • Stromal Cells / pathology
  • Tumor Microenvironment