title: Dormant tumor cells expressing LOXL2 acquire a stem-like phenotype mediating their transition to proliferative growth.
abstract: Recurrence of breast cancer disease years after treatment appears to arise from disseminated dormant tumor cells (DTC). The mechanisms underlying the outgrowth of DTC remain largely unknown. Here we demonstrate that dormant MCF-7 cells expressing LOXL2 acquire a cancer stem cell (CSC)-like phenotype, mediating their outgrowth in the 3D BME system that models tumor dormancy and outgrowth. Similarly, MCF-7-LOXL2 cells colonizing the lung transitioned from dormancy to metastatic outgrowth whereas MCF-7 cells remained dormant. Notably, epithelial to mesenchymal transition (EMT) of MCF-7-LOXL2 cells was required for their CSC-like properties and their transition to metastatic outgrowth. These findings were further supported by clinical data demonstrating that increase in LOXL2 mRNA levels correlates with increase in the mRNA levels of EMT and stem cells markers, and is also associated with decrease in relapse free survival of breast cancer patients. Notably, conditional hypoxia induced expression of endogenous LOXL2 in MCF-7 cells promoted EMT and the acquisition of a CSC-like phenotype, while knockdown of LOXL2 inhibited this transition. Overall, our results demonstrate that expression of LOXL2 endowed DTC with CSC-like phenotype driving their transition to metastatic outgrowth and this stem-like phenotype is dependent on EMT that can be driven by the tumor microenvironment.
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Weidenfeld
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Schif-Zuck
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Hanan
authors.initials: H
authors.lastname: Abu-Tayeh
authors.affiliation: Department of Microbiology, Dankook University, Cheonan, Republic of Korea.
authors.forename: Keunsoo
authors.initials: K
authors.lastname: Kang
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Kessler
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Marina
authors.initials: M
authors.lastname: Weissmann
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.affiliation: Department of Human Biology, University of Haifa, Haifa, Israel.
authors.forename: Dalit
authors.initials: D
authors.lastname: Barkan
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000502:physiology*; D010641:Phenotype; D059016:Tumor Microenvironment
chemical_list: D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human
keywords: LOXL2; breast cancer recurrence; cancer stem cells; dormant tumor cells; epithelial mesenchymal transition