Cancer Signalling and Metabolism Research Group’s Post

🌟 Integrin-Linked Kinase and Retinal Angiogenesis in FEVR 🌟 👁️ Familial Exudative Vitreoretinopathy (FEVR) is a challenging disease characterized by defective retinal angiogenesis, leading to vision complications. A study by Hongryeol Park, Hiroyuki Yamamoto, Lucas Mohn, Lea Ambühl, Kenichi Kanai, Inga Schmidt, Kee-Pyo Kim, Alessia Fraccaroli, Silke Feil, Harald Junge, Eloi Montanez, Wolfgang Berger, Ralf H. Adams investigates the role of integrin-linked kinase (ILK) in retinal angiogenesis and its connection to Wnt signaling and FEVR. 📊 Key Findings: ILK Role: ILK is crucial for retinal angiogenesis and maintaining the blood-retina barrier. Study Models: Inactivation of ILK in mice resulted in sprouting defects, reduced endothelial proliferation, and disruption of the blood-retina barrier, mirroring FEVR phenotypes. Human Impact: Mutations in ILK were identified in FEVR patients, affecting the gene product's function in vitro. 🔍 This research highlights the importance of ILK in retinal health and its potential link to Wnt signaling pathways, providing new insights into the molecular mechanisms underlying FEVR. 📚 Dive into the study to explore the detailed mechanisms and implications for clinical practice. https://lnkd.in/gariJA69 #MedicalResearch #FEVR #RetinalAngiogenesis #WntSignaling #ClinicalInsights #PhysicianUpdate #VisionHealth

Role of long-noncoding RNA in diabetic atherosclerosis Diabetes accelerates the development of atherosclerosis, increasing the incidence of cardiovascular events. In atherosclerosis, immune cells called macrophages release molecules such as chemokines and cytokines, causing inflammation and leading to arterial plaque formation. However, significant gaps persist in understanding the exact molecular mechanisms controlling this increased inflammatory response in individuals with diabetes. In a new, preclinical study, researchers identified a long non-coding RNA (lncRNA) sequence that could help them unravel the complex processes underlying diabetic atherosclerosis, potentially paving the way for future therapeutic interventions in humans. Through genetic analysis of a mouse model of diabetic atherosclerosis, the research team identified a specific sequence of long-noncoding RNA, they named MERRICAL, which is involved in recruiting macrophages to the arterial wall. As atherosclerosis progressed in these mice, the researchers found a notable increase in the expression of MERRICAL at arterial lesions—areas where atherosclerosis plaque built up and damaged the arteries. #ScienceMission #ScienceNewsHighlights https://lnkd.in/gyPzACqq

#HighlyCitedPapers--- 🎉 Genomic alterations in cholangiocarcinoma: clinical significance and relevance to therapy — Marianeve Carotenuto, Alessandra Sacco, Laura Forgione, Nicola Normanno*  📝 This review article summarizes the current knowledge on the genomic alterations of iCCA and eCCA, provide information on the main technologies for genomic profiling using either tumor tissue or cfDNA, and briefly discuss the main clinical trials with targeted agents in this disease. 👇Full text is available: https://lnkd.in/gJG9NZwP #Cholangiocarcinoma, #MolecularProfiling, #GenomicAlterations, #CirculatingTumorDNA #PubMed #Exploration of #Targeted #AntiTumor #Therapy 😆 Happy reading!

Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease   Schultheis N et al., 2024 DOI:https://lnkd.in/eWF-tiRX   Summary   We examined the function of heparan-sulfate-modified proteoglycans (HSPGs) in pathways affecting Alzheimer disease (AD)-related cell pathology in human cell lines and mouse astrocytes. Mechanisms of HSPG influences on presenilin-dependent cell loss were evaluated in Drosophila using knockdown of the presenilin homolog, Psn, together with partial loss-of-function of sulfateless (sfl), a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in human cell lines, Drosophila, and mouse astrocytes. RNA interference (RNAi) of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3, and APOE4. Neuron-directed knockdown of Psn in Drosophila produced apoptosis and cell loss in the brain, phenotypes suppressed by reductions in sfl expression. Abnormalities in mitochondria, liposomes, and autophagosome-derived structures in animals with Psn knockdown were also rescued by reduction of sfl. These findings support the direct involvement of HSPGs in AD pathogenesis. https://lnkd.in/ewF_B6-h

New study in Alzheimer's disease found, certain genes related to fat processing are active in glial cells. By studying brain tissue, a type of microglial cell with high levels of ACSL1, an enzyme linked to fat droplets, is identified. These ACSL1-positive microglia are most common in Alzheimer's patients with the APOE4/4 gene. In lab-grown microglia, APOE4 and fibrillar Aβ, a hallmark of Alzheimer's, trigger ACSL1 production, leading to fat droplet buildup. These fat-filled microglia release substances that harm neurons, especially in the presence of APOE4. Targeting fat filled microglia and underlying mechanism could guide new treatments for Alzheimer's disease. https://lnkd.in/e3-rgZHF

Exciting findings from the @SenesceX workshop! Manuel Serrano presented research highlighting Cyclophilin D's critical role in senescent cell survival. Check out Margherita Protasoni's study for more insights! https://lnkd.in/dM-9DRJQ ▶ Key findings include identifying CypD as a crucial mitochondrial target in senescent cells using CRISPR/Cas9 screening. This opens new avenues for senolytic therapies. ▶ CypD inhibition, whether genetic or pharmacological, is more lethal to senescent cells than non-senescent ones. This could revolutionize how we approach age-related diseases. ▶ The study highlights how CypD inhibition leads to mitochondrial calcium overload, triggering pyroptosis—a potential therapeutic target for eliminating senescent cells. ▶ Therapeutic implications are promising, with CypD as a novel senolytic target. Compounds like Cyclosporin A and NIM811 show significant in vitro and in vivo activity.#senescence

Is there a link between cardiac metabolism, dysfunctional mitochondria and atrial fibrillation? Find out here! https://lnkd.in/eMF-knpT Atrial fibrillation has a genomic basis on chromosome 4q25, close to the PITX2 gene. PITX2 deficiency has a variety of electrophysiological effects. This new study shows that deletion of PITX2 in atrial cardiomyocytes leads to mitochondrial dysfunction with reduced cardiomyocytes respiration. Could this be a treatable target to prevent atrial fibrillation and its progression?

Thrilled to share our group's latest publication in #NatureCommunications, titled "Single-cell transcriptional profile of CD34+ hematopoietic progenitor cells from del(5q) myelodysplastic syndromes and impact of lenalidomide" Using single cell RNA-seq on CD34+ progenitors from del(5q) MDS patients, we have identified cells harboring the deletion, characterizing the transcriptional impact of this genetic insult on disease pathogenesis and treatment response. Our results show that del(5q) and non-del(5q) cells share similar transcriptional alterations, with del(5q) cells presenting additional lesions. Moreover, hematological response to lenalidomide is associated with the reversal of some transcriptional lesions in both del(5q) and non-del(5q) cells. Thanks to all the people that have contributed to this study! https://lnkd.in/dkKzGddY

An analysis of Veracyte, Inc.'s Decipher Prostate in patients with de novo metastatic #ProstateCancer from a large-scale real-world clinical and transcriptomic data linkage was presented at #ASTRO24. Algorithms were developed to identify patients with de novo metastatic disease, and analysis identified that these patients tend to have higher PSA levels, very high Decipher scores, and specific mutations in tumor suppressor genes. This analysis and continued research is expected to enhance the understanding of de novo metastatic disease biology and inform treatment approaches. Click on the link to read more: https://lnkd.in/gaUJ3FuS

I am excited and honored to announce the publication of our new article "Rnf20-mediated transcriptional pausing and VEGFA splicing orchestrate vessel growth", now available in Nature Cardiovascular Research https://lnkd.in/eVP9-kDy The research uncovers a crucial role of Rnf20 in regulating the VEGF- Notch signaling pathways, which are not only essential for angiogenesis and tissue repair, but have also been linked to pathological angiogenesis. Specifically, we found that RNF20 controls Pol II promoter-proximal pausing, influencing key processes like RNA splicing, cell cycle regulation, and VEGF signaling. This has profound implications for angiogenic growth and vascular diseases. Importantly, loss of RNF20 results in increased VEGFA111 isoform production and altered Notch signaling, leading to uncontrolled tip cell specification—a critical factor in both physiological and pathological angiogenesis. This study could open doors to understanding how RNF20 mutations are linked to cardiovascular diseases and cancer, paving the way for potential therapeutic targets. I am grateful to be a part of this amazing work! A huge thanks to Gergana Dobreva, Nalan-Tetik-Elsherbiny and all the co-authors of this research. #vascularbiology #angiogenesis #cardiovascularresearch #Naturecardiovascularresearch #medicalfacultymannheim #heidelberguniversity