The impact of food availability on tumorigenesis is evolutionarily conserved.

The inability to control cell proliferation results in the formation of tumors in many multicellular lineages. Nonetheless, little is known about the extent of conservation of the biological traits and ecological factors that promote or inhibit tumorigenesis across the metazoan tree. Particularly, changes in food availability have been linked to increased cancer incidence in humans, as an outcome of evolutionary mismatch. Here, we apply evolutionary oncology principles to test whether food availability, regardless of the multicellular lineage considered, has an impact on tumorigenesis. We used two phylogenetically unrelated model systems, the cnidarian Hydra oligactis and the fish Danio rerio, to investigate the impact of resource availability on tumor occurrence and progression. Individuals from healthy and tumor-prone lines were placed on four diets that differed in feeding frequency and quantity. For both models, frequent overfeeding favored tumor emergence, while lean diets appeared more protective. In terms of tumor progression, high food availability promoted it, whereas low resources controlled it, but without having a curative effect. We discuss our results in light of current ideas about the possible conservation of basic processes governing cancer in metazoans (including ancestral life history trade-offs at the cell level) and in the framework of evolutionary medicine.

Murine AGM single-cell profiling identifies a continuum of hemogenic endothelium differentiation marked by ACE.

In vitro generation and expansion of hematopoietic stem cells (HSCs) holds great promise for the treatment of any ailment that relies on bone marrow or blood transplantation. To achieve this, it is essential to resolve the molecular and cellular pathways that govern HSC formation in the embryo. HSCs first emerge in the aorta-gonad-mesonephros (AGM) region, where a rare subset of endothelial cells, hemogenic endothelium (HE), undergoes an endothelial-to-hematopoietic transition (EHT). Here, we present full-length single-cell RNA sequencing (scRNA-seq) of the EHT process with a focus on HE and dorsal aorta niche cells. By using Runx1b and Gfi1/1b transgenic reporter mouse models to isolate HE, we uncovered that the pre-HE to HE continuum is specifically marked by angiotensin-I converting enzyme (ACE) expression. We established that HE cells begin to enter the cell cycle near the time of EHT initiation when their morphology still resembles endothelial cells. We further demonstrated that RUNX1 AGM niche cells consist of vascular smooth muscle cells and PDGFRa+ mesenchymal cells and can functionally support hematopoiesis. Overall, our study provides new insights into HE differentiation toward HSC and the role of AGM RUNX1+ niche cells in this process. Our expansive scRNA-seq datasets represents a powerful resource to investigate these processes further.

New reporter zebrafish line unveils heterogeneity among lymphatic endothelial cells during development.

BACKGROUND: In zebrafish, lymphatic endothelial cells (LECs) originate from multiple/several distinct progenitor populations and generate organ-specific lymphatic vasculatures. Cell fate and tissue specificities were determined using a combination of genetically engineered transgenic lines in which the promoter of a LEC-specific gene drives expression of a fluorescent reporter protein. RESULTS: We established a novel zebrafish transgenic line expressing eGFP under the control of part of the zebrafish batf3 promoter (Basic Leucine Zipper ATF-Like Transcription Factor 3). Spatiotemporal examination of Tg(batf3MIN:eGFP) transgenic fish revealed a typical lymphatic expression pattern, which does not perfectly recapitulate the expression pattern of existing LEC transgenic lines. eGFP+ cells constitute a heterogeneous endothelial cell population, which expressed LEC and/or blood endothelial cells (BEC) markers in different tissues. In addition, we characterize the renal eGFP+ cell as a population of interest to study kidney diseases and regeneration. CONCLUSION: Our Tg(batf3MIN:eGFP) reporter zebrafish line provides a useful system to study LEC populations, of which heterogeneity depends on origin of progenitors, tissue environment and physiological conditions. We further developed a novel fish-adapted tissue clearing method, which allows deep imaging and 3D-visualization of vascular and lymphatic networks in the whole organism.

Flotillin microdomains stabilize cadherins at cell-cell junctions.

Cadherins are essential in many fundamental processes and assemble at regions of cell-cell contact in large macromolecular complexes named adherens junctions. We have identified flotillin 1 and 2 as new partners of the cadherin complexes. We show that flotillins are localised at cell-cell junctions (CCJs) in a cadherin-dependent manner. Flotillins and cadherins are constitutively associated at the plasma membrane and their colocalisation at CCJ increases with CCJ maturation. Using three-dimensional structured illumination super-resolution microscopy, we found that cadherin and flotillin complexes are associated with F-actin bundles at CCJs. The knockdown of flotillins dramatically affected N- and E-cadherin recruitment at CCJs in mesenchymal and epithelial cell types and perturbed CCJ integrity and functionality. Moreover, we determined that flotillins are required for cadherin association with GM1-containing plasma membrane microdomains. This allows p120 catenin binding to the cadherin complex and its stabilization at CCJs. Altogether, these data demonstrate that flotillin microdomains are required for cadherin stabilization at CCJs and for the formation of functional CCJs.