ENPP1 Immunobiology as a Therapeutic Target Ruiz-Fernández de Córdoba, Borja; Martínez-Monge, Rafael; Lecanda, Fernando
Clinical cancer research,
06/2023, Letnik:
29, Številka:
12
Journal Article
Recenzirano
Odprti dostop
ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently ...overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic GMP-AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect, and their combination with other therapeutic modalities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor-immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state of the art and opens new perspectives for novel treatment strategies.
Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified ectonucleotide ...pyrophosphatase/phosphodiesterase 1/CD203a (ENPP1) to be closely associated with LRF. ENPP1hi circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of polymorphonuclear myeloid-derived suppressor cells and neutrophil extracellular trap (NET) formation. Genetic and pharmacologic ENPP1 inhibition or NET blockade extends relapse-free survival. Furthermore, in combination with fractionated irradiation, ENPP1 abrogation obliterates LRF. Mechanistically, ENPP1-generated adenosinergic metabolites enhance haptoglobin (HP) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse.
CTC exploit the ENPP1/HP axis to promote local recurrence post-surgery and post-irradiation by subduing myeloid suppressor cells in breast tumors. Blocking this axis impairs tumor engraftment, impedes immunosuppression, and obliterates NET formation, unveiling new opportunities for therapeutic intervention to eradicate local relapse and ameliorate patient survival. This article is highlighted in the In This Issue feature, p. 1171.
The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial‐based separation is a promising high‐throughput, marker‐free ...sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine‐tunable cut‐off value of 9 μm and a separation range of 2 μm. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirm highly efficient CTC isolation with a stringent cut‐off value and better separation results than the state of the art.
The data retrieved from satellite imagery and ground-based photometers are the two main sources of information on light pollution and are thus the two main tools for tackling the problem of ...artificial light pollution at night (ALAN). While satellite data offer high spatial coverage, on the other hand, photometric data provide information with a higher degree of temporal resolution. Thus, studying the proper correlation between both sources will allow us to calibrate and integrate them to obtain data with both high temporal resolution and spatial coverage. For this purpose, more than 15,000 satellite measurements and 400,000 measurements from 72 photometers for the year 2022 were used. The photometers used were the Sky-Glow Wireless Autonomous Sensor (SG-WAS) and Telescope Encoder and Sky Sensor WIFI (TESS-W) types, located at different ground-based locations, mainly in Spain. These photometers have a spectral sensitivity closer to that of VIIRS than to the Sky Quality Meter (SQM). In this study, a good correlation of data from the Day–Night Band (DNB) from the Visible Infrared Imaging Radiometer Suite (VIIRS) with a red photometric network between 19.41 mag/arcsec2 and 21.12 mag/arcsec2 was obtained.
Cholangiocarcinoma (CCA) is a neoplasia of the biliary tract driven by genetic, epigenetic and transcriptional mechanisms. Herein, we investigated the role of the transcription factor FOSL1, as well ...as its downstream transcriptional effectors, in the development and progression of CCA.
FOSL1 was investigated in human CCA clinical samples. Genetic inhibition of FOSL1 in human and mouse CCA cell lines was performed in in vitro and in vivo models using constitutive and inducible short-hairpin RNAs. Conditional FOSL1 ablation was done using a genetically engineered mouse (GEM) model of CCA (mutant KRAS and Trp53 knockout). Follow-up RNA and chromatin immunoprecipitation (ChIP) sequencing analyses were carried out and downstream targets were validated using genetic and pharmacological inhibition.
An inter-species analysis of FOSL1 in CCA was conducted. First, FOSL1 was found to be highly upregulated in human and mouse CCA, and associated with poor patient survival. Pharmacological inhibition of different signalling pathways in CCA cells converged on the regulation of FOSL1 expression. Functional experiments showed that FOSL1 is required for cell proliferation and cell cycle progression in vitro, and for tumour growth and tumour maintenance in both orthotopic and subcutaneous xenograft models. Likewise, FOSL1 genetic abrogation in a GEM model of CCA extended mouse survival by decreasing the oncogenic potential of transformed cholangiocytes. RNA and ChIP sequencing studies identified direct and indirect transcriptional effectors such as HMGCS1 and AURKA, whose genetic and pharmacological inhibition phenocopied FOSL1 loss.
Our data illustrate the functional and clinical relevance of FOSL1 in CCA and unveil potential targets amenable to pharmacological inhibition that could enable the implementation of novel therapeutic strategies.
Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention.
Display omitted
•The transcription factor FOSL1 is upregulated in human and mouse CCA, and is independently associated with patient survival.•Genetic FOSL1 inhibition impairs cell proliferation and cell cycle progression in vitro, and tumor initiation and maintenance in vivo.•The mevalonate pathway gene HMGCS1 is upregulated in human and mouse CCA, and its expression is controlled by direct FOSL1 promoter binding.•Genetic HMGCS1 abrogation or pharmacological blockade with mTOR inhibitors phenocopies loss of FOSL1.
To investigate intermediate-term clinical results in patients with concomitant anterior cruciate ligament (ACL) reconstruction and chondral defect treated with high-density autologous chondrocyte ...implantation (HD-ACI) compared to patients without ACL tear but with a chondral lesion and HD-ACI treatment.
Forty-eight patients with focal chondral lesions underwent HD-ACI (24 with ACL reconstruction after an ACL injury and 24 with an intact ACL). Follow-up assessments occurred at 6, 12, and 24 months. Patient-reported knee function and symptoms were assessed using the International Knee Documentation Committee (IKDC) questionnaire, pain was measured using the Visual Analog Scale (VAS), and adverse events were monitored. Physical activity was assessed using the Tegner Activity Level Scale, and cartilage healing was evaluated with the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score.
No significant adverse events occurred during follow-up. Both groups showed significant improvements at 2 years compared to baseline (VAS: 8.0 ± 1.3 to 1.4 ± 2.0 normal ACL; 7.4 ± 2.3 to 2.1 ± 2.3 ACL reconstruction; IKDC: 39.2 ± 10.6 to 76.1 ± 22.0 intact ACL; 35.6 ± 12.1 to 74.6 ± 20.9 ACL reconstruction). Patients in both groups exceeded the minimal clinically important difference (MCID) for IKDC scores. The Tegner Activity Level Scale decreased immediately after surgery and increased after 2 years, with 70.6% (normal ACL) and 89.5% (ACL reconstruction) returning to their preinjury activity levels. No significant differences in the MOCART score were observed between the groups.
ACL reconstruction does not appear to reduce the outcomes (at 2 years) of HD-ACI.
Study objective We seek to examine the efficacy and safety of prereperfusion emergency medical services (EMS)–administered intravenous metoprolol in anterior ST-segment elevation myocardial ...infarction patients undergoing eventual primary angioplasty. Methods This is a prespecified subgroup analysis of the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction trial population, who all eventually received oral metoprolol within 12 to 24 hours. We studied patients receiving intravenous metoprolol by EMS and compared them with others treated by EMS but not receiving intravenous metoprolol. Outcomes included infarct size and left ventricular ejection fraction on cardiac magnetic resonance imaging at 1 week, and safety by measuring the incidence of the predefined combined endpoint (composite of death, malignant ventricular arrhythmias, advanced atrioventricular block, cardiogenic shock, or reinfarction) within the first 24 hours. Results From the total population of the trial (N=270), 147 patients (54%) were recruited during out-of-hospital assistance and transferred to the primary angioplasty center (74 intravenous metoprolol and 73 controls). Infarct size was smaller in patients receiving intravenous metoprolol compared with controls (23.4 SD 15.0 versus 34.0 SD 23.7 g; adjusted difference –11.4; 95% confidence interval CI –18.6 to –4.3). Left ventricular ejection fraction was higher in the intravenous metoprolol group (48.1% SD 8.4% versus 43.1% SD 10.2%; adjusted difference 5.0; 95% CI 1.6 to 8.4). Metoprolol administration did not increase the incidence of the prespecified safety combined endpoint: 6.8% versus 17.8% in controls (risk difference –11.1; 95% CI –21.5 to –0.6). Conclusion Out-of-hospital administration of intravenous metoprolol by EMS within 4.5 hours of symptom onset in our subjects reduced infarct size and improved left ventricular ejection fraction with no excess of adverse events during the first 24 hours.
The circadian clock influences a number of cardiovascular (patho)physiological processes including the incidence of acute myocardial infarction. A circadian variation in infarct size has recently ...been shown in rodents, but there is no clinical evidence of this finding.
To determine the impact of time-of-day onset of ST segment elevation myocardial infarction (STEMI) on infarct size.
A retrospective single-centre analysis of 811 patients with STEMI admitted between 2003 and 2009 was performed. Infarct size was estimated by peak enzyme release. The relationship between peak enzyme concentrations and time-of-day were characterised using multivariate regression splines. Time of STEMI onset was divided into four 6-hour periods in phase with circadian rhythms.
Model comparisons based on likelihood ratio tests showed a circadian variation in infarct size across time-of-day as evaluated by peak creatine kinase (CK) and troponin-I (TnI) concentrations (p=0.015 and p=0.012, respectively). CK and TnI curves described similar patterns across time, with a global maximum in the 6:00-noon period and a local minimum in the noon-18:00 period. Infarct size was largest in patients with STEMI onset in the dark-to-light transition period (6:00-noon), with an increase in peak CK and TnI concentrations of 18.3% (p=0.031) and 24.6% (p=0.033), respectively, compared with onset of STEMI in the 18:00-midnight period. Patients with anterior wall STEMI also had significantly larger infarcts than those with STEMI in other locations.
Significant circadian oscillations in infarct size were found in patients according to time-of-day of STEMI onset. The infarct size was found to be significantly larger with STEMI onset in the dark-to-light transition period (6:00-noon). If confirmed, these results may have a significant impact on the interpretation of clinical trials of cardioprotective strategies in STEMI.
PDF
