Obesity triggers tumoral senescence and renders poorly immunogenic malignancies amenable to senolysis.

Obesity is a major risk factor for cancer. Conventional thought suggests that elevated adiposity predisposes to heightened inflammatory stress and potentiates tumor growth, yet underlying mechanisms remain ill-defined. Here, we show that tumors from patients with a body mass index >35 carry a high burden of senescent cells. In mouse syngeneic tumor models, we correlated a pronounced accretion of senescent cancer cells with poorly immunogenic tumors when mice were subjected to diet-induced obesity (DIO). Highly immunogenic tumors showed lesser senescence burden suggesting immune-mediated elimination of senescent cancer cells, likely targeted as a consequence of their senescence-associated secretory phenotype. Treatment with the senolytic BH3 mimetic small molecule inhibitor ABT-263 selectively stalled tumor growth in mice with DIO to rates comparable to regular diet-fed mice. Thus, consideration of body adiposity in the selection of cancer therapy may be a critical determinant for disease outcome in poorly immunogenic malignancies.

NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy.

Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from ß-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.

The protein tyrosine phosphatase PTPRJ/DEP-1 contributes to the regulation of the Notch-signaling pathway and sprouting angiogenesis.

The Dll4-Notch-signaling pathway regulates capillary sprouting via the specification of endothelial tip cells. While VEGF is a potent inducer of Dll4 expression, the intracellular mediators that stimulate its expression remain poorly defined. The protein tyrosine phosphatase PTPRJ/DEP-1 is required for angiogenesis in normal or pathological contexts through its modulation of VEGF signaling. Here, we show that in DEP-1 KO mice, retinas at post-natal day 5 show enlarged blood vessels, as well as an increased number of tip cells and vessel branching points at the migrating front of the vascular plexus. Consistent with these observations, the proliferation of endothelial cells is increased in the retinas of DEP-1 KO mice, as revealed by phospho-histone H3 staining, and increased phosphorylation of ERK1/2 in HUVECs transfected with DEP-1 siRNA. The expression of Dll4 was decreased in retinas of DEP-1 KO mice and was associated with decreased Notch activation. Mechanistically, reduced Dll4 expression in the absence of DEP-1 was correlated with the inhibition of the Src/Akt/ß-Catenin-signaling pathway in HUVECs. Conversely, overexpression of WT DEP-1 in cultured endothelial cells, but not of mutants unable to activate Src-dependent signaling, promoted Dll4 expression. Inhibition of Src, Akt, and ß-catenin transcriptional activity, leading to the inhibition of Dll4 expression, further suggested that their activation through a DEP-1-dependent pathway was required to promote Dll4 expression in VEGF-stimulated endothelial cells. Altogether, these data demonstrate that DEP-1, via Akt and ß-catenin, is a significant promoter of the VEGF-induced Dll4-Notch pathway, and can contribute to the regulation of the tip and stalk cell phenotypes of endothelial cells.

BMP9 (Bone Morphogenetic Protein-9)/Alk1 (Activin-Like Kinase Receptor Type I) Signaling Prevents Hyperglycemia-Induced Vascular Permeability.

Objective- Diabetic macular edema is a major cause of visual impairment. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. However, long-term intravitreal use of anti-VEGFs is associated with potential safety issues, and the identification of alternative regulators of vascular permeability may provide safer therapeutic options. The vascular specific BMP (bone morphogenetic protein) receptor ALK1 (activin-like kinase receptor type I) and its circulating ligand BMP9 have been shown to be potent vascular quiescence factors, but their role in the context of microvascular permeability associated with hyperglycemia has not been evaluated. Approach and Results- We investigated Alk1 signaling in hyperglycemic endothelial cells and assessed whether BMP9/Alk1 signaling could modulate vascular permeability. We show that high glucose concentrations impair Alk1 signaling, both in cultured endothelial cells and in a streptozotocin model of mouse diabetes mellitus. We observed that Alk1 signaling participates in the maintenance of vascular barrier function, as Alk1 haploinsufficiency worsens the vascular leakage observed in diabetic mice. Conversely, sustained delivery of BMP9 by adenoviral vectors significantly decreased the loss of retinal barrier function in diabetic mice. Mechanistically, we demonstrate that Alk1 signaling prevents VEGF-induced phosphorylation of VE-cadherin and induces the expression of occludin, thus strengthening vascular barrier functions. Conclusions- From these data, we suggest that by preventing retinal vascular permeability, BMP9 could serve as a novel therapeutic agent for diabetic macular edema.

Tumor angiogenesis and vascular normalization: alternative therapeutic targets.

Tumor blood vessels are a key target for cancer therapeutic management. Tumor cells secrete high levels of pro-angiogenic factors which contribute to the creation of an abnormal vascular network characterized by disorganized, immature and permeable blood vessels, resulting in poorly perfused tumors. The hypoxic microenvironment created by impaired tumor perfusion can promote the selection of more invasive and aggressive tumor cells and can also impede the tumor-killing action of immune cells. Furthermore, abnormal tumor perfusion also reduces the diffusion of chemotherapeutic drugs and radiotherapy efficiency. To fight against this defective phenotype, the normalization of the tumor vasculature has emerged as a new therapeutic strategy. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. In this review, we investigate the mechanisms involved in tumor angiogenesis and describe strategies used to achieve vascular normalization.

Endothelial RAF1/ERK activation regulates arterial morphogenesis.

Arterial morphogenesis is one of the most critical events during embryonic vascular development. Although arterial fate specification is mainly controlled by the Notch signaling pathway, arterial-venous patterning is modulated by a number of guidance factors. How these pathways are regulated is still largely unknown. Here, we demonstrate that endothelial activation of RAF1/extracellular signal-regulated kinase (ERK) pathway regulates arterial morphogenesis and arterial-venous patterning via Δ/Notch and semaphorin signaling. Introduction of a single amino acid RAF1 mutant (RAF1 Ser259Ala), which renders it resistant to inhibition by phosphorylation, into endothelial cells in vitro induced expression of virtually the entire embryonic arteriogenic program and activated semaphorin 6A-dependent endothelial cell-cell repulsion. In vivo, endothelial-specific expression of RAF1(S259A) during development induced extensive arterial morphogenesis both in the yolk sac and the embryo proper and disrupted arterial-venous patterning. Our results suggest that endothelial ERK signaling is critical for both arteriogenesis and arterial-venous patterning and that RAF1 Ser(259) phosphorylation plays a critical role in preventing unopposed ERK activation.

The H2.0-like homeobox transcription factor modulates yolk sac vascular remodeling in mouse embryos.

OBJECTIVE: The H2.0-like homeobox transcription factor (HLX) plays an essential role in visceral organogenesis in mice and has been shown to regulate angiogenic sprouting in vitro and in zebrafish embryos. We therefore examined the role of HLX in vascular development in mouse and avian embryos. APPROACH AND RESULTS: In situ hybridization showed that Hlx is expressed in a subset of sprouting blood vessels in postnatal mouse retinas and embryos. Hlx expression was conserved in quail embryos and upregulated in blood vessels at the onset of circulation. In vitro assays showed that Hlx is dynamically regulated by growth factors and shear stress alterations. Proangiogenic vascular endothelial growth factor induces Hlx expression in cultured endothelial cells, whereas signals that induce stalk cell identity lead to a reduction in Hlx expression. HLX was also downregulated in embryos in which flow was ablated, whereas injection of a starch solution, which increases blood viscosity and therefore shear stress, causes an upregulation in HLX. HLX knockdown in vitro resulted in a reduction in tip cell marker expression and in reduced angiogenic sprouting, but Hlx(-/-) embryos showed no defect in vascular sprouting at E8.5, E9.5, or E11.5 in vivo. Vascular remodeling of the capillary plexus was altered in Hlx(-/-) embryos, with a modestly enlarged venous plexus and reduction of the arterial plexus. CONCLUSIONS: Our findings indicate not only that Hlx regulates sprouting in vitro, but that its role in sprouting is nonessential in vivo. We find HLX is regulated by shear stress and a subtle defect in vascular remodeling is present in knockout embryos.

Endothelial signaling and the molecular basis of arteriovenous malformation.

Arteriovenous malformations occur when abnormalities of vascular patterning result in the flow of blood from arteries to veins without an intervening capillary bed. Recent work has revealed the importance of the Notch and TGF-ß signaling pathways in vascular patterning. Specifically, Notch signaling has an increasingly apparent role in arterial specification and suppression of branching, whereas TGF-ß is implicated in vascular smooth muscle development and remodeling under angiogenic stimuli. These physiologic roles, consequently, have implicated both pathways in the pathogenesis of arteriovenous malformation. In this review, we summarize the studies of endothelial signaling that contribute to arteriovenous malformation and the roles of genes implicated in their pathogenesis. We further discuss how endothelial signaling may contribute to vascular smooth muscle development and how knowledge of signaling pathways may provide us targets for medical therapy in these vascular lesions.

Involvement of neuronal factors in tumor angiogenesis and the shaping of the cancer microenvironment.

Emerging evidence suggests that nerves within the tumor microenvironment play a crucial role in regulating angiogenesis. Neurotransmitters and neuropeptides released by nerves can interact with nearby blood vessels and tumor cells, influencing their behavior and modulating the angiogenic response. Moreover, nerve-derived signals may activate signaling pathways that enhance the production of pro-angiogenic factors within the tumor microenvironment, further supporting blood vessel growth around tumors. The intricate network of communication between neural constituents and the vascular system accentuates the potential of therapeutically targeting neural-mediated pathways as an innovative strategy to modulate tumor angiogenesis and, consequently, neoplastic proliferation. Hereby, we review studies that evaluate the precise molecular interplay and the potential clinical ramifications of manipulating neural elements for the purpose of anti-angiogenic therapeutics within the scope of cancer treatment.

Endothelial nuclear factor-κB-dependent regulation of arteriogenesis and branching.

BACKGROUND: Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation, and network size. Factors regulating these processes have not been determined. METHODS AND RESULTS: We used an inhibitor of NFκB activation (IκBαSR) under control of an endothelial-specific inducible promoter to selectively suppress endothelial nuclear factor-κB activation during development, in the adult vasculature, or in vitro. Inhibition of nuclear factor-κB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecule expression leading to decreased monocyte influx, reduced hypoxia-inducible factor-1α levels, and a marked decrease in δ-like ligand 4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching as treatment with Jagged-1 peptide reduced the size of the arterial network to baseline levels. CONCLUSIONS: These findings identify nuclear factor-κB as a key regulator of adult and developmental arteriogenesis and collateral formation. Nuclear factor-κB achieves this by regulating hypoxia-inducible factor-1α-dependent expression of vascular endothelial growth factor-A and platelet-derived growth factor-BB, which are necessary for the development and maturation of the arterial collateral network, and by regulating δ-like ligand 4 expression, which in turn determines the size and complexity of the network.

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe.

In brief: The mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates the crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby regulating the endothelial cell behavior and temporal dynamics of their identity during sprouting angiogenesis. Highlights: Bmp9 upregulates the expression of LFng in endothelial cells.LFng regulates the temporal dynamics of tip/stalk selection and rearrangement.LFng indicated to play a role in hereditary hemorrhagic telangiectasia.Bmp9 and LFng mediate the endothelial cell-pericyte crosstalk.Bone Morphogenic Protein 9 (Bmp9), whose signaling through Activin receptor-like kinase 1 (Alk1) is involved in several diseases, has been shown to independently activate Notch target genes in an additive fashion with canonical Notch signaling. Here, by integrating predictive computational modeling validated with experiments, we uncover that Bmp9 upregulates Lunatic Fringe (LFng) in endothelial cells (ECs), and thereby also regulates Notch activity in an inter-dependent, multiplicative fashion. Specifically, the Bmp9-upregulated LFng enhances Notch receptor activity creating a much stronger effect when Dll4 ligands are also present. During sprouting, this LFng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement. Our results further indicate that LFng can play a role in Bmp9-related diseases and in pericyte-driven vessel stabilization, since we find LFng contributes to Jag1 upregulation in Bmp9-stimulated ECs; thus, Bmp9-upregulated LFng results in not only enhanced EC Dll4-Notch1 activation, but also Jag1-Notch3 activation in pericytes.

Identification and functional analysis of endothelial tip cell-enriched genes.

Sprouting of developing blood vessels is mediated by specialized motile endothelial cells localized at the tips of growing capillaries. Following behind the tip cells, endothelial stalk cells form the capillary lumen and proliferate. Expression of the Notch ligand Delta-like-4 (Dll4) in tip cells suppresses tip cell fate in neighboring stalk cells via Notch signaling. In DLL4(+/-) mouse mutants, most retinal endothelial cells display morphologic features of tip cells. We hypothesized that these mouse mutants could be used to isolate tip cells and so to determine their genetic repertoire. Using transcriptome analysis of retinal endothelial cells isolated from DLL4(+/-) and wild-type mice, we identified 3 clusters of tip cell-enriched genes, encoding extracellular matrix degrading enzymes, basement membrane components, and secreted molecules. Secreted molecules endothelial-specific molecule 1, angiopoietin 2, and apelin bind to cognate receptors on endothelial stalk cells. Knockout mice and zebrafish morpholino knockdown of apelin showed delayed angiogenesis and reduced proliferation of stalk cells expressing the apelin receptor APJ. Thus, tip cells may regulate angiogenesis via matrix remodeling, production of basement membrane, and release of secreted molecules, some of which regulate stalk cell behavior.

TGF-ß Superfamily Signaling in the Eye: Implications for Ocular Pathologies.

The TGF-ß signaling pathway plays a crucial role in several key aspects of development and tissue homeostasis. TGF-ß ligands and their mediators have been shown to be important regulators of ocular physiology and their dysregulation has been described in several eye pathologies. TGF-ß signaling participates in regulating several key developmental processes in the eye, including angiogenesis and neurogenesis. Inadequate TGF-ß signaling has been associated with defective angiogenesis, vascular barrier function, unfavorable inflammatory responses, and tissue fibrosis. In addition, experimental models of corneal neovascularization, diabetic retinopathy, proliferative vitreoretinopathy, glaucoma, or corneal injury suggest that aberrant TGF-ß signaling may contribute to the pathological features of these conditions, showing the potential of modulating TGF-ß signaling to treat eye diseases. This review highlights the key roles of TGF-ß family members in ocular physiology and in eye diseases, and reviews approaches targeting the TGF-ß signaling as potential treatment options.

Brain arteriovenous malformation in hereditary hemorrhagic telangiectasia: Recent advances in cellular and molecular mechanisms.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by vessel dilatation, such as telangiectasia in skin and mucosa and arteriovenous malformations (AVM) in internal organs such as the gastrointestinal tract, lungs, and brain. AVMs are fragile and tortuous vascular anomalies that directly connect arteries and veins, bypassing healthy capillaries. Mutations in transforming growth factor ß (TGFß) signaling pathway components, such as ENG (ENDOGLIN), ACVRL1 (ALK1), and SMAD4 (SMAD4) genes, account for most of HHT cases. 10-20% of HHT patients develop brain AVMs (bAVMs), which can lead to vessel wall rupture and intracranial hemorrhages. Though the main mutations are known, mechanisms leading to AVM formation are unclear, partially due to lack of animal models. Recent mouse models allowed significant advances in our understanding of AVMs. Endothelial-specific deletion of either Acvrl1, Eng or Smad4 is sufficient to induce AVMs, identifying endothelial cells (ECs) as primary targets of BMP signaling to promote vascular integrity. Loss of ALK1/ENG/SMAD4 signaling is associated with NOTCH signaling defects and abnormal arteriovenous EC differentiation. Moreover, cumulative evidence suggests that AVMs originate from venous ECs with defective flow-migration coupling and excessive proliferation. Mutant ECs show an increase of PI3K/AKT signaling and inhibitors of this signaling pathway rescue AVMs in HHT mouse models, revealing new therapeutic avenues. In this review, we will summarize recent advances and current knowledge of mechanisms controlling the pathogenesis of bAVMs, and discuss unresolved questions.

Guidance of vascular development: lessons from the nervous system.

The vascular system of vertebrates consists of an organized, branched network of arteries, veins, and capillaries that penetrates all the tissues of the body. One of the most striking features of the vascular system is that its branching pattern is highly stereotyped, with major and secondary branches forming at specific sites and developing highly conserved organ-specific vascular patterns. The factors controlling vascular patterning are not yet completely understood. Recent studies have highlighted the anatomic and structural similarities between blood vessels and nerves. The 2 networks are often aligned, with nerve fibers and blood vessels following parallel routes. Furthermore, both systems require precise control over their guidance and growth. Several molecules with attractive and repulsive properties have been found to modulate the proper guidance of both nerves and blood vessels. These include the Semaphorins, the Slits, and the Netrins and their receptors. In this review, we describe the molecular mechanisms by which blood vessels and axons achieve proper path finding and the molecular cues that are involved in their guidance.

Diabetic Kidney Disease, Endothelial Damage, and Podocyte-Endothelial Crosstalk.

Diabetes-related complications are a significant source of morbidity and mortality worldwide. Diabetic kidney disease is a frequent microvascular complication and a primary cause of kidney failure in patients with diabetes. The glomerular filtration barrier is composed of 3 layers: the endothelium, glomerular basement membrane, and podocytes. Podocytes and the endothelium communicate through molecular crosstalk to maintain filtration at the glomerular filtration barrier. Chronic hyperglycemia affects all 3 layers of the glomerular filtration barrier, as well as the molecular crosstalk that occurs between the 2 cellular layers. One of the earliest events following chronic hyperglycemia is endothelial cell dysfunction. Early endothelial damage is associated with progression of diabetic kidney disease. However, current therapies are based in controlling glycemia and arterial blood pressure without targeting endothelial dysfunction. Disruption of the endothelial cell layer also alters the molecular crosstalk that occurs between the endothelium and podocytes. This review discusses both the physiologic and pathologic communication that occurs at the glomerular filtration barrier. It examines how these signaling components contribute to podocyte foot effacement, podocyte detachment, and the progression of diabetic kidney disease.

Roles and mechanisms of BAP1 deubiquitinase in tumor suppression.

The BAP1 gene has emerged as a major tumor suppressor mutated with various frequencies in numerous human malignancies, including uveal melanoma, malignant pleural mesothelioma, clear cell renal cell carcinoma, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, and thymic epithelial tumors. BAP1 mutations are also observed at low frequency in other malignancies including breast, colorectal, pancreatic, and bladder cancers. BAP1 germline mutations are associated with high incidence of mesothelioma, uveal melanoma, and other cancers, defining the "BAP1 cancer syndrome." Interestingly, germline BAP1 mutations constitute an important paradigm for gene-environment interactions, as loss of BAP1 predisposes to carcinogen-induced tumorigenesis. Inactivating mutations of BAP1 are also identified in sporadic cancers, denoting the importance of this gene for normal tissue homeostasis and tumor suppression, although some oncogenic properties have also been attributed to BAP1. BAP1 belongs to the deubiquitinase superfamily of enzymes, which are responsible for the maturation and turnover of ubiquitin as well as the reversal of substrate ubiquitination, thus regulating ubiquitin signaling. BAP1 is predominantly nuclear and interacts with several chromatin-associated factors, assembling multi-protein complexes with mutually exclusive partners. BAP1 exerts its function through highly regulated deubiquitination of its substrates. As such, BAP1 orchestrates chromatin-associated processes including gene expression, DNA replication, and DNA repair. BAP1 also exerts cytoplasmic functions, notably in regulating Ca2+ signaling at the endoplasmic reticulum. This DUB is also subjected to multiple post-translational modifications, notably phosphorylation and ubiquitination, indicating that several signaling pathways tightly regulate its function. Recent progress indicated that BAP1 plays essential roles in multiple cellular processes including cell proliferation and differentiation, cell metabolism, as well as cell survival and death. In this review, we summarize the biological and molecular functions of BAP1 and explain how the inactivation of this DUB might cause human cancers. We also highlight some of the unresolved questions and suggest potential new directions.

Hydroxychloroquine (HCQ) decreases the benefit of anti-PD-1 immune checkpoint blockade in tumor immunotherapy.

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.

COCO/DAND5 inhibits developmental and pathological ocular angiogenesis.

Neovascularization contributes to multiple visual disorders including age-related macular degeneration (AMD) and retinopathy of prematurity. Current therapies for treating ocular angiogenesis are centered on the inhibition of vascular endothelial growth factor (VEGF). While clinically effective, some AMD patients are refractory or develop resistance to anti-VEGF therapies and concerns of increased risks of developing geographic atrophy following long-term treatment have been raised. Identification of alternative pathways to inhibit pathological angiogenesis is thus important. We have identified a novel inhibitor of angiogenesis, COCO, a member of the Cerberus-related DAN protein family. We demonstrate that COCO inhibits sprouting, migration and cellular proliferation of cultured endothelial cells. Intravitreal injections of COCO inhibited retinal vascularization during development and in models of retinopathy of prematurity. COCO equally abrogated angiogenesis in models of choroidal neovascularization. Mechanistically, COCO inhibited TGFß and BMP pathways and altered energy metabolism and redox balance of endothelial cells. Together, these data show that COCO is an inhibitor of retinal and choroidal angiogenesis, possibly representing a therapeutic option for the treatment of neovascular ocular diseases.

Starvation-induced proteasome assemblies in the nucleus link amino acid supply to apoptosis.

Eukaryotic cells have evolved highly orchestrated protein catabolic machineries responsible for the timely and selective disposal of proteins and organelles, thereby ensuring amino acid recycling. However, how protein degradation is coordinated with amino acid supply and protein synthesis has remained largely elusive. Here we show that the mammalian proteasome undergoes liquid-liquid phase separation in the nucleus upon amino acid deprivation. We termed these proteasome condensates SIPAN (Starvation-Induced Proteasome Assemblies in the Nucleus) and show that these are a common response of mammalian cells to amino acid deprivation. SIPAN undergo fusion events, rapidly exchange proteasome particles with the surrounding milieu and quickly dissolve following amino acid replenishment. We further show that: (i) SIPAN contain K48-conjugated ubiquitin, (ii) proteasome inhibition accelerates SIPAN formation, (iii) deubiquitinase inhibition prevents SIPAN resolution and (iv) RAD23B proteasome shuttling factor is required for SIPAN formation. Finally, SIPAN formation is associated with decreased cell survival and p53-mediated apoptosis, which might contribute to tissue fitness in diverse pathophysiological conditions.