RT Journal Article
SR Electronic
T1 Single-cell RNAseq uncovers involution mimicry as an aberrant development pathway during breast cancer metastasis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 624890
DO 10.1101/624890
A1 Fatima Valdes-Mora
A1 Robert Salomon
A1 Brian Gloss
A1 Andrew MK. Law
A1 Kendelle Murphy
A1 Daniel L. Roden
A1 Lesley Castillo
A1 Yolanda Colino-Sanguino
A1 Zoya Kikhtyak
A1 Nona Farbehi
A1 James RW. Conway
A1 Samantha R. Oakes
A1 Thomas Cox
A1 Paul Timpson
A1 Christopher J. Ormandy
A1 David Gallego-Ortega
YR 2019
UL http://biorxiv.org/content/early/2019/05/03/624890.abstract
AB Single-cell RNA-seq has emerged as a powerful method to unravel heterogeneity of complex biological systems; this has enabled in vivo characterization of cell type compositions through unsupervised sampling and modelling of transcriptional states in single cells. Here we used the high-throughput microfluidic-based single-cell RNA-seq method Drop-seq to elucidate the cellular composition and functional diversity of breast tumours during the induction of metastatic disease in a transgenic model related to pregnancy-associated breast cancer (PABC). We characterised with unprecedented definition, how the activation of developmental programs associated to pregnancy results in the acquisition of an aggressive phenotype. We show that cancer cells are classified in a structure comparable with the lineages of the epithelial mammary gland hierarchy, revealing high dynamics and plasticity of cancer cells during disease progression. This cancer progression program is orchestrated by alveolar milk secretory cells, that in conjunction with cell types from the tumour microenvironment (TME), including cancer-associated fibroblasts (CAFs), form a multi-cellular process that resembles an aberrant involution. Finally, we analysed the interactome of the tumour ecosystem to define a high-resolution landscape of the molecular pathways of cell-to-cell communication that underpins extra-cellular remodelling and inflammation associated with the aggressive involution mimicry.In conclusion, our study recapitulates developmental mechanisms that have gone awry during carcinogenesis in a model of PABC. We provide a large-scale single-cell transcriptional landscape of breast tumours that allows unprecedented understanding of breast heterogeneity and deep analysis of key molecular events that result in cancer malignancy.