Highlights of This Issue

Abstract

The oncogenic epithelial-to-mesenchymal transition (EMT) contributes to tumor progression in several ways, including resistance to anoikis, resulting in metastatic potential. Here, an interesting mechanism is described for EMT to confer anoikis resistance. Through the up-regulation of glutamate dehydrogenase, EMT enhances mitochondrial metabolism, while simultaneously reducing reactive oxygen species (ROS), thereby protecting against anoikis. These effects are reversed by the master programmer of the epithelial phenotype, Grainyhead-like 2 (GRHL2). These results demonstrate that EMT and mesenchymal-to-epithelial (MET) regulate anoikis through metabolic pathways that are amenable to pharmacologic intervention.This study conclusively demonstrates the central role played by the chemokine receptor CX3CR1 in the seeding and colonization of the skeleton by breast cancer cells and also reports the synthesis, functional characterization and pre-clinical validation of a new small-molecule inhibitor of CX3CR1. Interfering with CX3CR1 activation dramatically impairs both spreading and growth of existing metastases in animal models. As emerging evidence emphasizes the impact that the cross-seeding of existing metastases exerts on clinical progression, blocking the seeding and initial colonization of new lesions by inhibiting CX3CR1 could prevent, decelerate or even stabilize metastatic breast cancer.Here, Zhang and colleagues, from the Duke Cancer Institute, have developed a novel circulating tumor cell (CTC) detection platform, modified from the original Janssen Cellsearch assay, to detect c-MET amplified tumor cells from the blood. The investigators developed and validated their CTC assay in appropriate healthy volunteers and spiked cell line controls. Importantly, the study also identified patients with metastatic gastric, renal, colorectal, and bladder cancer with detectable MET-amplified CTCs. This novel CTC capture approach serves as a predictive biomarker for future studies involving c-MET pathway inhibitors in patients with advanced solid tumors.Protein Tyrosine Kinase 6 (PTK6) promotes epithelial differentiation in the gastrointestinal tract and skin, while membrane-associated active PTK6 promotes oncogenic signaling in breast and prostate tumors. Mathur and colleagues report that PTK6 maintains the epithelial phenotype of colon cancer cells in a kinase-independent manner and PTK6 expression decreases during colon cancer progression. However, kinase active PTK6 is also able to promote oncogenic signaling in these same cells. Understanding the distinct context-dependent adaptor and kinase functions of PTK6 is critical for determining its potential as a therapeutic target.