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PLoS Biol. 2018 Jun 20;16(6):e2004049. doi: 10.1371/journal.pbio.2004049. eCollection 2018 Jun.

Reporters to mark and eliminate basal or luminal epithelial cells in culture and in vivo.

Author information

1
Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
2
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
3
Princess Margaret Cancer Centre, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
4
Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
5
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
6
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States of America.
7
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

Abstract

The contribution of basal and luminal cells to cancer progression and metastasis is poorly understood. We report generation of reporter systems driven by either keratin-14 (K14) or keratin-8 (K8) promoter that not only express a fluorescent protein but also an inducible suicide gene. Transgenic mice express the reporter genes in the right cell compartments of mammary gland epithelia and respond to treatment with toxins. In addition, we engineered the reporters into 4T1 metastatic mouse tumor cell line and demonstrate that K14+ cells, but not K14- or K8+, are both highly invasive in three-dimensional (3D) culture and metastatic in vivo. Treatment of cells in culture, or tumors in mice, with reporter-targeting toxin inhibited both invasive behavior and metastasis in vivo. RNA sequencing (RNA-seq), secretome, and epigenome analysis of K14+ and K14- cells led to the identification of amphoterin-induced protein 2 (Amigo2) as a new cell invasion driver whose expression correlated with decreased relapse-free survival in patients with TP53 wild-type (WT) breast cancer.

PMID:
29924804
PMCID:
PMC6042798
DOI:
10.1371/journal.pbio.2004049
[Indexed for MEDLINE]
Free PMC Article

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