Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Summary Tumor-secreted extracellular vesicles (EVs) are critical mediators of intercellular communication between tumor cells and stromal cells in local and distant microenvironments. Accordingly, EVs play an essential role in both primary tumor growth and metastatic evolution. EVs orchestrate multiple systemic pathophysiological processes, such as coagulation, vascular leakiness, and reprogramming of stromal recipient cells to support pre-metastatic niche formation and subsequent metastasis. Clinically, EVs may be biomarkers and novel therapeutic targets for cancer progression, particularly for predicting and preventing future metastatic development.

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.

Chromatin state and oncogenic competence Although specific DNA mutations can lead to tumor generation, they are not transforming in all cellular contexts. This may be due to the intrinsic transcriptional program present in the cell of origin. Using zebrafish and human pluripotent stem cell cancer models, Baggiolini et al . report that neural crest cells and melanoblasts (precursors to melanocytes) are susceptible to specific mutation of the BRAF gene, whereas melanocytes are relatively resistant (see the Perspective by Vredevoogd and Peeper). The competent cells display higher levels of chromatin factors such as the protein ATAD2 compared with the less competent ones. ATAD2 forms a complex with the neural crest transcription factor SOX10 and establishes a chromatin state that makes them permissive to BRAF mutagenesis. These data indicate that developmental chromatin programs are a determinant of how cells respond to DNA mutations. —BAP

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention in a variety of cancers. Here, we will review iron homeostasis in non-malignant and malignant cells, the widespread effects of iron depletion on the cell, the various iron chelators that have been explored in the treatment of cancer, and the tumor types that have been most commonly studied in the context of iron chelation.

During tumor progression, cancer cells come into contact with new cell types in the microenvironment, but it is unclear how tumor cells adapt to new environments. Here, we integrate spatial transcriptomics and scRNA-seq to characterize tumor/microenvironment interactions during the initial steps of invasion. Using a zebrafish model of melanoma, we identify a unique "interface" cell state at the tumor/microenvironment boundary. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. An ETS-driven interface is conserved across ten patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatial transcriptomic approaches in uncovering mechanisms that allow tumors to invade into the microenvironment.

Lipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets in vertebrate models rely on static imaging or the use of fluorescent dyes, limiting investigation of their rapid in vivo dynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparent casper zebrafish enabled in vivo imaging of adipose depots responsive to nutrient deprivation and high-fat diet. Simultaneously, we performed a large-scale in vitro chemical screen of 1280 compounds and identified several novel regulators of lipolysis in adipocytes. Using our Tg(-3.5ubb:plin2-tdTomato) zebrafish line, we validated several of these novel regulators and revealed an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts using chemical, dietary, or genetic perturbations.

Human verbal language communicates both manifest and latent messages concerning the speaker's world and behavior. To understand his world and analyze his problems,(1) it is important to decode the latent messages as they may hint at the root causes. The authors present a discourse analysis of a prisoner's text and a semantic and morphological analysis of it. This text reflects contempt for the law and its representatives, together with a weak attachment to legitimate society, neutralization of personal responsibility, denial of guilt, and low self-esteem. Sociolinguistic and psycholinguistic analysis points toward a more profound evaluation of the perceptions and world of the speaker. It seems that he yearns for attachment, for understanding and social acceptance, and perhaps even to abandon crime. The prisoner's latent feelings of helplessness and fear of humiliation may help the therapist establish a therapeutic relationship and help him change his perceptions and behavior.