In non-small cell lung cancer (NSCLC), receptor tyrosine kinases (RTKs) stand out among causal dominant oncogenes, and the ablation of RTK signaling has emerged as a novel tailored therapeutic strategy. Nonetheless, long-term RTK inhibition leads invariably to acquired resistance, tumor recurrence and metastatic dissemination. In ALK+ cell lines, inhibition of ALK signaling was associated with coactivation of several RTKs, whose pharmacological suppression reverted the partial resistance to ALK blockade. Remarkably, ERBB2 signaling synergized with ALK and contributed to the neoplastic phenotype. Moreover, the engagement of wild-type epidermal growth factor receptor or MET receptors could sustain cell viability through early growth response 1 (EGR1) and/or Erk1/2; Akt activation and EGR1 overexpression prevented cell death induced by combined ALK/RTK inhibition. Membrane expression of ERBB2 in a subset of primary naive ALK+ NSCLC could be relevant in the clinical arena. Our data demonstrate that the neoplastic phenotype of ALK-driven NSCLC relays ‘ab initio' on the concomitant activation of multiple RTK signals via autocrine/paracrine regulatory loops. These findings suggest that molecular and functional signatures are required in de novo lung cancer patients for the design of efficacious and multi-targeted ‘patient-specific' therapies.

Targeted imaging requires site-specific accumulation of a contrast agent (CA), and the properties of that agent must be selected according to the abundance of the target to obtain a signal above the detection limit of the instrument. However

Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non‐small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non‐bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti‐LIGHT or RANK–fragment crystallizable region (RANK‐Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC‐1. After intratibial implantation, wild‐type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14−/− mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. © 2019 American Society for Bone and Mineral Research.

Key Points Rac1 and Cdc42 possess nonredundant roles in preventing apoptosis of NPM-ALK lymphoma cells. Simultaneous deletions of both Rac1 and Cdc42 prevents NPM-ALK lymphoma dissemination in vivo.

In vitro labelling of cells permits incorporation of large amounts of iron oxide and consequently high detection sensitivity, but it remains controversial whether labelled cells would respond normally to stimuli. This question was addressed by differentiating bone marrow-derived macrophages (BMDMs) in vitro, labelling cells with high concentrations of Endorem in vitro, and eliminating unlabelled cells by magnetic enrichment. To explore their acute inflammatory response, enriched cells were injected into mice with carrageenan-induced inflammation, the 'air pouch model'. Cells recovered from the inflammation site 16 h after intravenous BMDM injection into the tail vein were analysed by in vitro MRI and fluorescent microscopy. With both assays, Endorem-labelled cells were detectable. This indicates that BMDMs, loaded with high concentrations of iron oxide in vitro, can still respond to chemokine gradients and infiltrate inflamed tissue in mice. Furthermore, by using genetically modified mice as BMDM donors, it should be possible to study the role of individual genes in macrophage recruitment.