Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivoand are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB, and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146-dependent manner.

Store-operated Ca²⁺ entry (SOCE) controls Ca²⁺ homeostasis and mediates multiple Ca²⁺-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca²⁺ sensor STIM1 and the plasma membrane Ca²⁺ channel ORAI1. STIM1 and ORAI1 gain-of-function (GoF) mutations induce SOCE overactivity and excessive Ca²⁺ influx, leading to tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and a variable occurrence of multi-systemic anomalies affecting spleen, skin, and platelets. To date, different STIM1 mouse models exist, but only a single ORAI1 mouse model with muscle-specific TAM/STRMK phenotype has been described, precluding a comparative analysis of the physiopathology in all affected tissues. Here, we generated and characterized mice harboring a prevalent ORAI1 TAM/STRMK mutation and we provide phenotypic, physiological, biochemical, and functional data. Examination of Orai1^V109M/+ mice revealed smaller size, spleen enlargement, reduced muscle force, and decreased platelet numbers. Morphological analyses of muscle sections evidenced the presence of tubular aggregates, the histopathological hallmark on biopsies from TAM/STRMK patients absent in all reported STIM1 models. Overall, Orai1^V109M/+ mice reliably recapitulate the human disorder and highlight the primary physiological defects caused by ORAI1 gain-of-function mutations. They also provide the possibility to investigate the formation of tubular aggregates and to develop a common therapy for different TAM/STRMK forms.

The coordination of chromosome segregation with cytokinesis is crucial for maintaining genomic stability. Chromatin bridges, arising from DNA replication stress or catenated chromosomes, can interfere with this process, leading to genomic instability if not properly resolved. Here, we uncover that the budding yeast DNA helicase Srs2 is essential for delaying abscission in the presence of chromatin bridges, thereby preventing chromosome breakage during cytokinesis. We also find that its human paralog PARI delays abscission-associated events, including midbody severing and actin-patch disassembly, in human cells with chromatin bridges. Although PARI depletion does not lead to increased bridge breakage or binucleation, our data indicate that PARI has nonessential functions within the Aurora B–mediated abscission checkpoint pathway. These findings establish a key role of Srs2 in NoCut checkpoint signaling in yeast, and suggest a functionally related role of PARI in coordinating abscission timing with chromatin bridge resolution in human cells.

Aggregation and self‐assembly of nuclear coactivator binding domain of CREB‐binding protein was studied under different experimental conditions. Single l ‐ or d ‐enantiomers fold into left‐ or right‐handed helical structures at neutral pH while β‐sheet amyloid arrangement occurs under acidic conditions. Mixtures of both enantiomers promote self‐assembly into amyloid β‐sheet structures highlighting the role of chirality in the formation of thermodynamically more stable racemic β‐sheet structures. Fore more information, see the Full Paper by V. Torbeev et al. on page 9889 ff.

Cellular senescence is a state of stable arrest and secretion linked to aging and disease. Here we identify that senescent cells dispose of large fragments of themselves through cell-to-cell adhesion, which we term senescent-cell adhesion fragments (SCAFs). Found across all senescent types examined, SCAFs lack nuclear material but contain organelles, including damaged mitochondria. Disrupting adherens junctions decreased SCAF formation but induced senescent-cell death, which was caused by an inability to shed damaged mitochondria. Dynamic analyses show that SCAFs ultimately rupture, releasing a complex proteome including damage-associated molecular patterns (DAMPs) and proteins linked to neurodegenerative disease. Functionally, SCAFs activate wound-healing and cancer-related programs, promoting migration and invasion. Altogether, these findings identify a new feature that facilitates senescent cell survival, but the consequence of which is external deposition of damaged intracellular contents, with implications for cancer and aging.