Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells

By Devon A. Lawson, N. Bhakta, K. Kessenbrock, Karin D Prummel, Ying Yu, K. Takai, A. Zhou, Henok Eyob, S. Balakrishnan, Chih-Yang Wang and 3 more. Nature, 2015

825 citations recorded by the source corpus.

Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated by stem-like cells that proliferate and differentiate to produce advanced metastatic disease.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/d755d403929c73143750392a081fa7bff1390d3c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Molecular Biology

In Oncology

Citations in the corpus

Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer (2017, neutral): “Carcinoma cells variably expressed aggressive cancer signatures such as epithelial–mesenchymal transition (EMT), stemness, angiogenesis, proliferation 29,30 and recurrence 3,31 (Supplementary Fig.”
EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, positive): “…single-cell expression analyses have been applied to DTCs isolated from the organs of patient-derived xenograft (PDX) models of breast cancer; some organs harbored low-burden metastatic disease due to the presence of small numbers of ostensibly dormant carcinoma cells (Lawson et al., 2015).”
Epithelial-mesenchymal plasticity in cancer progression and metastasis (2019, background): “This association is also confirmed experimentally in circulating pancreatic tumor cells and metastatic breast cancer cells in vivo, which have undergone EMT, express cancer stem cell-associated markers and exhibit stem cell properties (Lawson et al., 2015; Rhim et al., 2012).”
Identifying phenotype-associated subpopulations by integrating bulk and single-cell sequencing data (2021, neutral): “Cancer cells are heterogeneous and include subpopulations such as cancer stem cells, which are known to drive tumor progression and poor prognosis 16, 17 .”