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
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.