Explore the vast range of titles available.

Replication stress (RS) is a major source of genomic instability and is intrinsic to cancer cells. RS is also the consequence of chemotherapeutic drugs for treating cancer. However, adaptation to RS is also a mechanism of resistance to chemotherapy. BRCA2 deficiency results in replication stress in human cells. BRCA2 protein’s main functions include DNA repair by homologous recombination (HR) both at induced DNA double-strand breaks (DSB) and spontaneous replicative lesions. At stalled replication forks, BRCA2 protects the DNA from aberrant nucleolytic degradation and is thought to limit the appearance of ssDNA gaps by arresting replication and via post-replicative HR. However, whether and how BRCA2 acts to limit the formation of ssDNA gaps or mediate their repair, remains ill-defined. Here, we use breast cancer variants affecting different domains of BRCA2 to shed light on this function. We demonstrate that the N-terminal DNA binding domain (NTD), and specifically, its dsDNA binding activity, is required to prevent and repair/fill-in ssDNA gaps upon nucleotide depletion but not to limit PARPi-induced ssDNA gaps. Thus, these findings suggest that nucleotide depletion and PARPi trigger gaps via distinct mechanisms and that the NTD of BRCA2 prevents nucleotide depletion-induced ssDNA gaps. Here the authors demonstrate that the dsDNA binding function at the N-terminus of BRCA2 prevents nucleotide depletion-dependent replicative ssDNA gaps but not those induced by PARP inhibition. This function is impaired in breast-cancer variants affecting this region.

Germline monoallelic truncating mutations in BRCA2, a key mediator of homologous recombination (HR), predispose individuals to breast and ovarian cancer. Tumorigenesis is typically attributed to biallelic inactivation, yet evidence suggests haploinsufficiency can suffice in some contexts. We model two pathogenic BRCA2 truncating variants in heterozygosis in non-tumorigenic breast epithelial cells. One variant is not expressed and confers PARP inhibitor (PARPi) sensitivity and reduced HR, indicating haploinsufficiency. In contrast, the other produces a truncated protein that rewires transcription in cells and tumors. Mechanistically, this truncated product acts as a dominant negative by forming abnormal oligomers with full-length BRCA2 and sequestering the PCAF acetyltransferase. This interaction reduces global histone H4 acetylation and suppresses NF-κB transcriptional activity, ultimately altering epithelial migration. Our findings reveal a BRCA2–PCAF axis that modulates NF-κB signaling, a process co-opted by a recurrent BRCA2 pathogenic variant. Pathogenic BRCA2 truncating variants in heterozygosis drive distinct cancer-linked mechanisms. Here the authors show that one causes PARPi sensitivity and HR loss via haploinsufficiency, while another expresses a truncated protein that rewires transcription by hijacking PCAF, reducing H4 acetylation and NF-κB activity.

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells. Cancer associated fibroblasts (CAFs) have been suggested to regulate cancer cell metabolism, but the mechanisms are not completely elucidated. Here, the authors show that low FAK expression in stromal cells correlates with poor prognosis in breast and pancreatic cancer patients and that FAK-silencing in CAFs promotes tumourigenesis by the paracrine regulation of cancer cell metabolism.

The overexpression of the protein tyrosine kinase, Focal adhesion kinase (FAK), in endothelial cells has implicated its requirement in angiogenesis and tumour growth, but how pericyte FAK regulates tumour angiogenesis is unknown. We show that pericyte FAK regulates tumour growth and angiogenesis in multiple mouse models of melanoma, lung carcinoma and pancreatic B-cell insulinoma and provide evidence that loss of pericyte FAK enhances Gas6-stimulated phosphorylation of the receptor tyrosine kinase, Axl with an upregulation of Cyr61, driving enhanced tumour growth. We further show that pericyte derived Cyr61 instructs tumour cells to elevate expression of the proangiogenic/protumourigenic transmembrane receptor Tissue Factor. Finally, in human melanoma we show that when 50% or more tumour blood vessels are pericyte-FAK negative, melanoma patients are stratified into those with increased tumour size, enhanced blood vessel density and metastasis. Overall our data uncover a previously unknown mechanism of tumour growth by pericytes that is controlled by pericyte FAK. Focal adhesion kinase (FAK) is required for tumour angiogenesis and growth. Here, the authors show that deletion of pericyte FAK upregulates Gas6-Axl mediated Cyr61 production, which increases endothelial cell proliferation and angiogenesis, while elevating tissue factor production to enhance tumour cell proliferation.

A functional blood vessel network is required to deliver oxygen and nutrients to the cancer cells for their growth. Angiogenesis, the formation of new blood vessels from pre-existing ones, is one of the major mechanisms to create this vascular network. Anti-angiogenic therapy was conceived as the inhibition of the cellular and molecular players involved in tumor angiogenesis such as vascular endothelial growth factor and its main receptors. Due to limitations of this therapy, different approaches of vessel modulation such as vascular normalization or vascular promotion have been studied showing benefits in different tumor models and clinical trials. In contrast to anti-angiogenic therapy, which inhibits the blood vessels that are being formed, vascular disruption therapy aims to destroy already formed tumor vessels. These malignant vascular structures differ from other blood vessels in terms of endothelial cell states, pericyte coverage and basement membrane development. The molecules used for vascular disruption are microtubule-binding molecules, flavonoids that induce endothelial cell apoptosis or molecules vectorized to endothelial receptors. Many vascular disruption agents have been tested in clinical trials showing some promising results, but with some limitations that include resistant rim cells or the development of hypoxia that induces cancer regrowth and poor delivery of the anti-tumor agents. The main objective of this review is to focus on vascular disruption agents therapy, novel molecules, new ways to overcome therapy resistance to them, current clinical status and, especially, the upcoming challenges and applications of these molecules.

Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.

Germline monoallelic truncating mutations in BRCA2, a critical mediator of homologous recombination (HR), predispose individuals to breast and ovarian cancer. While tumorigenesis is usually attributed to biallelic inactivation, emerging evidence suggests that haploinsufficiency may suffice in certain contexts. To investigate this, we recreated two BRCA2 pathogenic truncating variants in heterozygosis in non-tumorigenic breast epithelial cells. Cells carrying a truncating mutation that was not produced prompted sensitivity to PARP inhibitors (PARPi) and reduced the HR capacity indicating haploinsufficiency. Surprisingly, the other variant was expressed as a truncated product and prompted a transcriptional rewiring. Mechanistically, the truncated BRCA2 product formed abnormal oligomers with full-length BRCA2 and bound to the PCAF acetyltransferase, sequestering it. This led to reduced global histone H4 acetylation and decreased NF-κB transcriptional activity, ultimately impairing epithelial cell migration—a process also altered in tumors. Our findings uncover a previously unrecognized BRCA2–PCAF axis that modulates NF-κB-driven transcriptional program, a process that is co-opted by a recurrent BRCA2 pathogenic variant.

The Anthropocene era demands a future alternative to the current state of play. The aim of this study is to analyze spatial and climate governance and policy through a critical geographical study of the island of Mallorca (Spain), an example of the model of urban development and tourism growth that has generated acute environmental impacts. Beginning with the European Union and Spain, the work then narrows its focus to the case study of Mallorca. The study is based on a review of the academic literature, statistical sources, and an analysis of the content of spatial and climate policy in Spain and the Balearic Islands. The work reflects on the flawed spatial planning responses to climate change and outlines strategies to adopt more radical measures for effective climate action. The work identifies six main shortcomings and makes proposals to tackle the challenges of the Anthropocene in Mallorca, responding to each of the deficiencies detected. The article seeks to encourage reflection and proposes key strategies for spatial governance and climate policy to lend coherence to the fight against climate change.

Prospective long-term data after retinopathy of prematurity (ROP) treatment with anti-vascular endothelial growth factor injections vs laser therapy are scarce. The FIREFLEYE (Aflibercept for ROP IVT Injection vs Laser Therapy) next trial is prospectively evaluating the long-term efficacy and safety outcomes following ROP treatment with intravitreal aflibercept vs laser therapy. To evaluate 2-year ophthalmic and safety outcomes after 0.4-mg aflibercept injection or laser therapy in the 24-week randomized (2:1) FIREFLEYE trial (FIREFLEYE outcomes previously reported). This prospective nonrandomized controlled trial performed in 24 countries in Asia, Europe, and South America (2020-2025) follows up participants treated in the FIREFLEYE randomized clinical trial (2019-2021) through 5 years of age. Participants included children born very or extremely preterm (gestational age ≤32 weeks) or with very or extremely low birth weight (≤1500 g) who were previously treated with a 0.4-mg injection of aflibercept compared with laser therapy for severe acute-phase ROP. Data for the present interim analysis were acquired from March 18, 2020, to July 25, 2022. Complications of ROP treated at investigator discretion (no study treatment). Efficacy end points included ROP status, unfavorable structural outcomes, ROP recurrence, treatment for ROP complications, completion of vascularization, and visual function. Safety end points included adverse events and growth and neurodevelopmental outcomes. Overall, 100 children were enrolled (median gestational age, 26 [range, 23-31] weeks; 53 boys and 47 girls). Of these, 21 were Asian, 2 were Black, 75 were White, and 2 were of more than 1 race. At 2 years of age, 61 of 63 children (96.8%) in the aflibercept group vs 30 of 32 (93.8%) in the laser group had no ROP. Through 2 years of age, 62 of 66 (93.9%) in the aflibercept group and 32 of 34 (94.1%) in the laser group had no unfavorable structural outcomes. No new retinal detachment occurred during the study. Four children in the aflibercept group (6.1%) were treated for ROP complications before 1 year of age (2 had preexisting end-stage disease and total retinal detachment; 1 had reactivated plus disease; and 1 had recurrent retinal neovascularization not further specified). Most children were able to fix and follow a 5-cm toy (aflibercept group, 118 of 122 eyes [96.7%] among 63 children; laser group, 62 of 63 eyes [98.4%] among 33 children). High myopia was present in 9 of 115 eyes (7.8%) among 5 children in the aflibercept group and 13 of 60 eyes (21.7%) among 9 children in the laser group. No relevant differences in growth and neurodevelopmental outcomes by Bayley Scales of Infant and Toddler Development, Third Edition and Vineland Adaptive Behavior Scales, Second Edition were identified. In this nonrandomized follow-up of a randomized clinical trial comparing treatment of severe acute-phase ROP with 0.4-mg injection of aflibercept and laser, disease control was stable and visual function was appropriate in children through 2 years of age. No adverse effects on safety, including growth and neurodevelopment, were identified. These findings provide clinically relevant long-term information on intravitreal aflibercept injection therapy for ROP. ClinicalTrials.gov Identifier: NCT04015180.