Biology subjects

Tisch, N.

Publications and source records attributed to Tisch, N..

3 recordsLinked to original sources

bioRxiv2025

Context-dependent response of endothelial cells to PIK3CA mutation

Cancer mutations in the PIK3CA gene cause congenital disorders. The endothelium is among the most frequently affected tissues in these disorders, displaying aberrant vascular overgrowth in the form of malformations. Pathological PIK3CA vascular phenotypes are found in veins and capillaries but rarely in arteries for reasons that are unclear at present. Here, using lineage tracing, we show that expression of mutated PIK3CAH1047R in endothelial cells leads to marked clonal expansions in capillary and venous endothelial cells. In contrast, mature arterial endothelial cells are refractory to PIK3CA mutation under these conditions and never display pathological phenotypes. Moreover, PIK3CAH1047Rexpression in arterial precursors interrupts arterial differentiation, thereby driving fate switch towards venous identity. This fate rewiring offers an additional layer of protection to prevent arterial damage in response to PIK3CA genetic perturbation. Molecularly, the PIK3CAH1047R-driven arterial-to-venous fate switch is orchestrated by upregulation of the vein-specifying transcription factor Nr2f2/COUP-TFII. Our findings reveal that pathogenic responses to PIK3CAH1047Rgreatly depend on the diferentation stage and fate trajectory of the targeted cell. Arteries are thus shielded against PIK3CA mutation, solving the long-standing question on the rarity of PIK3CA-related arterial malformations observed in patients.

developmental biology↗

bioRxiv2020

Malaria parasites differentially sense environmental elasticity during transmission

Transmission of malaria-causing parasites to and by the mosquito rely on active parasite migration and constitute bottlenecks in the Plasmodium life cycle. Parasite adaption to the biochemically and physically different environments must hence be a key evolutionary driver for transmission efficiency. To probe how subtle but physiologically relevant changes in environmental elasticity impact parasite migration, we introduce 2D and 3D polyacrylamide gels to study ookinetes, the parasite forms emigrating from the mosquito blood meal and sporozoites, the forms transmitted to the vertebrate host. We show that ookinetes adapt their migratory path but not their speed to environmental elasticity and are motile for over 24 hours on soft substrates. In contrast, sporozoites evolved more short-lived rapid gliding motility for rapidly crossing the skin. Strikingly, sporozoites are highly sensitive to substrate elasticity possibly to avoid adhesion on soft endothelial cells on their long way to the liver. Hence the two migratory stages of Plasmodium evolved different strategies to overcome the physical challenges posed by the respective environments and barriers they encounter. HighlightsPlasmodium ookinetes can move for over 24 hours on very soft substrates mimicking the blood meal Plasmodium ookinetes change their migration path according to substrate stiffness Plasmodium sporozoites are highly sensitive to subtle changes in substrate elasticity Sporozoite may have evolved to not attach to the soft endothelium to help reach the liver

biophysics↗

bioRxiv2019

Caspase-8 Modulates Angiogenesis By Regulating A Cell Death Independent Pathway In Endothelial Cells

During developmental angiogenesis blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates both cell death via apoptosis and necroptosis. Here we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal angiogenesis. EC specific Casp-8 knockout pups (Casp-8ECko) have reduced retinal angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting and migration independent of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 mitogen-activated protein kinase (MAPK) downstream of receptorinteracting serine/threonine-protein kinase 3 (RIPK3) and destabilization of VE-cadherin at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR), resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs is beneficial, as pathological neovascularization was reduced in Casp-8ECko pups. Taken together, we identify that Casp-8 signals in a cell-death independent manner in ECs during postnatal and pathological blood vessel formation.

developmental biology↗