Beschreibung:
<jats:p>During intravasation, circulating tumor cells (<jats:styled-content style="fixed-case">CTC</jats:styled-content>s) detach from the epithelium of origin and begin the epithelial‐to‐mesenchymal transition (<jats:styled-content style="fixed-case">EMT</jats:styled-content>) process, where they lose epithelial features and pass through the endothelium to enter circulation. Although detachment from the extracellular matrix is a strong source of metabolic stress, which induces anoikis, <jats:styled-content style="fixed-case">CTC</jats:styled-content>s can survive. Recently, the tumor suppressor liver kinase B1 (<jats:styled-content style="fixed-case">LKB</jats:styled-content>1) has gained attention for its role as a proto‐oncogene in restoring the correct <jats:styled-content style="fixed-case">ATP</jats:styled-content>/<jats:styled-content style="fixed-case">AMP</jats:styled-content> ratio during metabolic stress. The aim of this study was to assess <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 expression in epithelial‐negative <jats:styled-content style="fixed-case">CTC</jats:styled-content>s isolated from patients with metastatic breast cancer and to characterize its possible association with <jats:styled-content style="fixed-case">EMT</jats:styled-content> and stemness features. Transcriptome analysis of Ep<jats:styled-content style="fixed-case">CAM</jats:styled-content>‐negative <jats:styled-content style="fixed-case">CTC</jats:styled-content>s indicated that over 25% of patients showed enhanced <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 levels, while almost 20% of patients showed enhanced levels of an <jats:styled-content style="fixed-case">EMT</jats:styled-content> transcription factor known as <jats:styled-content style="fixed-case">ZEB</jats:styled-content>1. Transcriptome and immunofluorescence analyses showed that patients with enhanced <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 were correspondingly <jats:styled-content style="fixed-case">ZEB</jats:styled-content>1 negative, suggesting complementary activity for the two proteins. Only <jats:styled-content style="fixed-case">ZEB</jats:styled-content>1 was significantly associated with cancer stem cell (<jats:styled-content style="fixed-case">CSC</jats:styled-content>) markers. Neither <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 nor <jats:styled-content style="fixed-case">ZEB</jats:styled-content>1 upregulation showed a correlation with clinical outcome, while enhanced levels of stemness‐associated <jats:styled-content style="fixed-case">CD</jats:styled-content>44 correlated with a lower progression‐free and overall survival. <jats:italic>Ex vivo</jats:italic> models showed that <jats:styled-content style="fixed-case">MDA</jats:styled-content>‐<jats:styled-content style="fixed-case">MB</jats:styled-content>‐231, a mesenchymal tumor cell line, grew in suspension only if <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 was upregulated, but the <jats:styled-content style="fixed-case">MCF</jats:styled-content>‐7 epithelial cell line lost its ability to generate spheroids and colonies when <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 was inhibited, supporting the idea that <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 might be necessary for <jats:styled-content style="fixed-case">CTC</jats:styled-content>s to overcome the absence of the extracellular matrix during the early phases of intravasation. If these preliminary results are confirmed, <jats:styled-content style="fixed-case">LKB</jats:styled-content>1 will become a novel therapeutic target for eradicating metastasis‐initiating <jats:styled-content style="fixed-case">CTC</jats:styled-content>s from patients with primary breast cancer.</jats:p>