Microreviews
CircRNA regulates the liquid-liquid phase separation of ATG4B, a novel strategy to inhibit cancer metastasis?
Ziyuan Guo1,#, Yang Chen1,#, Yaran Wu1 and Jiqin Lian1
Metastasis is the leading cause of death in cancer patients. Currently, there are no effective treatments to prevent cancer metastases. Therefore, it is imperative to provide more effective biomarkers and
Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook
Shing Fai Chan1, Keyur Vora1 and Rohan Dharmakumar1,*
Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical (...)
Unraveling the surface proteomic profile of multiple myeloma to reveal new immunotherapeutic targets and markers of drug resistance
Bonell Patiño-Escobar1, Ian D. Ferguson1,2, Arun P. Wiita1,3,4
The cell surface proteome (“surfaceome”) serves as the interface between diseased cells and their local microenvironment. In cancer, this compartment is critical not only for defining tumor biology but also serves as a rich source of potential therapeutic targets and diagnostic markers. Recently, we profiled the surfaceome of the blood cancer multiple myeloma, an incurable plasma cell malignancy. While available small molecule agents can drive initial remissions in myeloma, resistance inevitably occurs. Several new classes of immunotherapies targeting myeloma surface antigens, including antibody therapeutics and chimeric antigen receptor (CAR) T-cells, can further prolong survival. However, new approaches are still needed for those who relapse. We thus applied the glycoprotein cell surface capture (CSC) methodology to panel of multiple myeloma cell lines, identifying key surface protein features of malignant plasma cells. We characterized the most (...)
COX-2 upregulation by tumour cells post-chemotherapy fuels the immune evasive dark side of cancer inflammation
Charlotte R. Bell1 and Santiago Zelenay1,2
Cytotoxic therapies, such as chemotherapy and radiotherapy, are mainstays of cancer treatment for both early and unresectable, advanced disease. In addition to debulking the tumour mass through direct killing of proliferating tumour cells, these treatments can promote tumour control via immune-stimulating effects. Nonetheless, chemoresistance and tumour relapse remain huge clinical problems, suggesting that induction of anti-cancer immunity post-cytotoxic therapy is often weak, not durable and/or overcome by immune evasive mechanisms. In our recent study (Nat Commun 13:2063), we demonstrate that cancer cell-intrinsic activation of the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway post-chemotherapy treatment is a prevalent phenomenon which profoundly alters the inflammatory properties of the treated cancer cells. Of particular translational relevance, our findings support a model whereby upregulation of COX-2 expression (...)
Could TNF-antagonists be a novel treatment strategy for BPH patients?
Renee E. Vickman1, Omar E. Franco1 and Simon W. Hayward1
Tumor necrosis factor (TNF) is widely recognized as a pivotal player in both systemic and local inflammatory processes. Due to the critical role this molecule has in driving both chronic and acute inflammation, it was among the earliest therapeutic targets utilized for pa-tients with autoimmune (AI) diseases. While inflamma-tion in the prostate is commonly observed, the organ has not previously been considered a target of systemic inflammation associated with some AI diseases. In pa-tients with benign prostatic hyperplasia (BPH), chronic inflammation is common, and immune cells represent a significant proportion of cells in the organ. Accumulation of inflammatory cells may be a response to an initial in-sult and/or a factor in driving BPH pathogenesis. Cer-tainly, inflammation can limit the efficacy of existing medical therapies in these patients. We previously showed that a pattern of gene expression in BPH tissues from patients who had progressed to indication-specific surgery was consistent with the changes seen in AI dis-eases. Recently, we demonstrated that patients with AI disease have an approximately 50% increase in (...)
A pathological role of the Hsp40 protein Ydj1/DnaJA1 in models of Alzheimer’s disease
Jelena Tadic1,2, Julia Ring1, Andrea Jerkovic1, Selena Ristic1, Marta Maglione3,4, Jörn Dengjel5, Stephan J. Sigrist3,4 and Tobias Eisenberg1,2,6
Alzheimer’s disease (AD) is the most common form of dementia with millions of people affected worldwide. Pathophysiological manifestations of AD include the extracellular accumulation of amyloid beta (Abeta) peptides, products of the proteolytic cleavage of the amyloid precursor protein APP. Increasing evidence suggests that Abeta peptides also accumulate intracellularly, triggering neurotoxic events such as mitochondrial dysfunction. However, the molecular factors driving formation and toxicity of intracellular Abeta are poorly understood. In our recent study [EMBO Mol Med 2022 – e13952], we used different eukaryotic model systems to identify such factors. Based on a genetic screen in yeast and subsequent molecular analyses, we found that both the yeast chaperone Ydj1 and its human ortholog DnaJA1 physically interact with Abeta, facilitate the aggregation of Abeta (...)
GRASPing the unconventional secretory machinery to bridge cellular stress signaling to the extracellular proteome
Constantinos Demetriades1,2, Julian Nüchel1 and Markus Plomann3
Part of the cellular response to stress is an evolutionarily conserved, poorly-understood process called unconventional protein secretion (UPS). Although cells shut down conventional/bulk secretion to save resources upon stress, UPS
Ribosome traffic jam in neurodegeneration: decoding hurdles in Huntington disease
Srinivasa Subramaniam1
The symptoms of HD, a neurodegenerative disorder, are severe disruption of cognitive and motor functions, including changes in posture and gait. HTT, the gene responsible for HD, is CAG (codes