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.
Highlights
Carcinomas are defined as cancers of epithelial cell origin
If not all, cancer-related deaths result from metastasis
The differentiation states of the cancer epithelial cells are thought to be a critical determinant of metastasis
Summary
Carcinomas are defined as cancers of epithelial cell origin. All carcinomas contain cancer cells in multiple differentiation statuses such as luminal and basal. Keratins (cytokeratins, abbreviated as K) are intermediate filament proteins that are expressed in a differentiation status–specific manner in luminal (K7, K8, K18, K19) or basal (K5, K6, K14, K17) epithelial cells and are routinely used as diagnostic markers for cancer tissues [1,2]. It is thought that cancer epithelia are plastic to an extent and can interconvert between basal and luminal differentiation states during initiation, progression of cancer, and in response to treatment [3]. There is a significant need for experimental model systems that facilitate the study of this plasticity and assess the importance of the epithelial differentiation state in modulating the biology of cancer cells. Understanding the key molecular determinants that regulate the metastatic process is fundamental to identifying ways to limit the spread of and to target metastatic breast cancer
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