ABSTRACT
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.
Subject(s)
Cancer-Associated Fibroblasts/metabolism , Carcinoma, Basal Cell/genetics , Mammary Glands, Animal/metabolism , Mammary Neoplasms, Animal/genetics , Transcriptome , Animals , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cancer-Associated Fibroblasts/pathology , Carcinoma, Basal Cell/metabolism , Carcinoma, Basal Cell/pathology , Cell Lineage/genetics , Chemokine CXCL12/genetics , Chemokine CXCL12/metabolism , Collagen Type I, alpha 1 Chain/genetics , Collagen Type I, alpha 1 Chain/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix/pathology , Female , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Mammary Glands, Animal/pathology , Mammary Glands, Animal/virology , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Animal/pathology , Mammary Tumor Virus, Mouse/growth & development , Mammary Tumor Virus, Mouse/pathogenicity , Matrix Metalloproteinase 3/genetics , Matrix Metalloproteinase 3/metabolism , Mice , Neoplasm Metastasis , Pregnancy , Single-Cell Analysis , Tumor Microenvironment/geneticsABSTRACT
Breast cancers are complex cellular ecosystems where heterotypic interactions play central roles in disease progression and response to therapy. However, our knowledge of their cellular composition and organization is limited. Here we present a single-cell and spatially resolved transcriptomics analysis of human breast cancers. We developed a single-cell method of intrinsic subtype classification (SCSubtype) to reveal recurrent neoplastic cell heterogeneity. Immunophenotyping using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) provides high-resolution immune profiles, including new PD-L1/PD-L2+ macrophage populations associated with clinical outcome. Mesenchymal cells displayed diverse functions and cell-surface protein expression through differentiation within three major lineages. Stromal-immune niches were spatially organized in tumors, offering insights into antitumor immune regulation. Using single-cell signatures, we deconvoluted large breast cancer cohorts to stratify them into nine clusters, termed 'ecotypes', with unique cellular compositions and clinical outcomes. This study provides a comprehensive transcriptional atlas of the cellular architecture of breast cancer.