With the advent of effective tools to study lipids, including mass spectrometry-based lipidomics, lipids are emerging as central players in cancer biology. Lipids function as essential building ...blocks for membranes, serve as fuel to drive energy-demanding processes and play a key role as signaling molecules and as regulators of numerous cellular functions. Not unexpectedly, cancer cells, as well as other cell types in the tumor microenvironment, exploit various ways to acquire lipids and extensively rewire their metabolism as part of a plastic and context-dependent metabolic reprogramming that is driven by both oncogenic and environmental cues. The resulting changes in the fate and composition of lipids help cancer cells to thrive in a changing microenvironment by supporting key oncogenic functions and cancer hallmarks, including cellular energetics, promoting feedforward oncogenic signaling, resisting oxidative and other stresses, regulating intercellular communication and immune responses. Supported by the close connection between altered lipid metabolism and the pathogenic process, specific lipid profiles are emerging as unique disease biomarkers, with diagnostic, prognostic and predictive potential. Multiple preclinical studies illustrate the translational promise of exploiting lipid metabolism in cancer, and critically, have shown context dependent actionable vulnerabilities that can be rationally targeted, particularly in combinatorial approaches. Moreover, lipids themselves can be used as membrane disrupting agents or as key components of nanocarriers of various therapeutics. With a number of preclinical compounds and strategies that are approaching clinical trials, we are at the doorstep of exploiting a hitherto underappreciated hallmark of cancer and promising target in the oncologist's strategy to combat cancer.
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The precise role of 5'AMP-activated kinase (AMPK) in cancer and its potential as a therapeutic target is controversial. Although it is well established that activation of this energy sensor inhibits ...the main anabolic processes that sustain cancer cell proliferation and growth, AMPK activation can confer on cancer cells the plasticity to survive under metabolic stress such as hypoxia and glucose deprivation, which are commonly observed in fast growing tumors. Thus, AMPK is referred to as both a "conditional" tumor suppressor and "contextual" oncogene. To add a further layer of complexity, AMPK activation in human cancer tissues and its correlation with tumor aggressiveness and progression appears to vary in different contexts. The current review discusses the different faces of this metabolic regulator, the therapeutic implications of its modulation, and provides an overview of the most relevant data available on AMPK activation and AMPK-activating drugs in human studies.
Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. ...In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
LSD1 Ellis, Leigh; Loda, Massimo
Proceedings of the National Academy of Sciences - PNAS,
05/2018, Volume:
115, Issue:
18
Journal Article
Peer reviewed
Open access
Ellis and Loda comments on the article LSD1 activates a lethal prostate cancer gene network independently of its demethylase function by A. Sehrawat and colleagues. They say that an important finding ...from Sehrawat and colleagues is that LSD1's activation of a lethal prostate cancer gene network comprised of specific master regulator transcription factors was independent of its demethylase function. They also say that the article provides novel mechanism underlying the progression of lethal prostate cancer and may provide a road forward to target a subset of these lethal cases.
COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil ...extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.
c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on ...prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.
Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate ...cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.
Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8
cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors.
Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells;
= 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8
cells (
= 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors.
A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic.
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The deubiquitinating enzyme USP2a has shown oncogenic properties in many cancer types by impairing ubiquitination of FASN, MDM2, MDMX or Aurora A. Aberrant expression of USP2a has been linked to ...progression of human tumors, particularly prostate cancer. However, little is known about the role of USP2a or its mechanism of action in bladder cancer. Here, we provide evidence that USP2a is an oncoprotein in bladder cancer cells. Enforced expression of USP2a caused enhanced proliferation, invasion, migration and resistance to several chemotherapeutic reagents, while USP2a loss resulted in slower proliferation, greater chemosensitivity and reduced migratory/invasive capability compared with control cells. USP2a, but not a catalytically inactive mutant, enhanced proliferation in immortalized TRT-HU1 normal human bladder epithelial cells. USP2a bound to cyclin A1 and prevented cyclin A1 ubiquitination, leading to accumulation of cyclin A1 by a block in degradation. Enforced expression of wild type USP2a, but not an inactive USP2a mutant, resulted in cyclin A1 accumulation and increased cell proliferation. We conclude that USP2a impairs ubiquitination and stabilizes an important cell cycle regulator, cyclin A1, raising the possibility of USP2a targeting as a therapeutic strategy against bladder tumors in combination with chemotherapy.
Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies ...frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.
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