1. Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype.
- Author
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Valdés-Mora F, Salomon R, Gloss BS, Law AMK, Venhuizen J, Castillo L, Murphy KJ, Magenau A, Papanicolaou M, Rodriguez de la Fuente L, Roden DL, Colino-Sanguino Y, Kikhtyak Z, Farbehi N, Conway JRW, Sikta N, Oakes SR, Cox TR, O'Donoghue SI, Timpson P, Ormandy CJ, and Gallego-Ortega D
- Subjects
- 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 genetics, Cancer-Associated Fibroblasts metabolism, Carcinoma, Basal Cell genetics, Mammary Glands, Animal metabolism, Mammary Neoplasms, Animal genetics, Transcriptome
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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