Search results for "Gens"
showing 10 items of 3762 documents
Molecular Engineering Strategies Tailoring the Apoptotic Response to a MET Therapeutic Antibody
2020
The MET oncogene encodes a tyrosine kinase receptor involved in the control of a complex network of biological responses that include protection from apoptosis and stimulation of cell growth during embryogenesis, tissue regeneration, and cancer progression. We previously developed an antagonist antibody (DN30) inducing the physical removal of the receptor from the cell surface and resulting in suppression of the biological responses to MET. In its bivalent form, the antibody displayed a residual agonist activity, due to dimerization of the lingering receptors, and partial activation of the downstream signaling cascade. The balance between the two opposing activities is variable in different…
Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis.
2018
Summary Metastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here, we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of cerebellar degeneration-related 1 antisense (CDR1as), a regulator of miR-7, as a hallmark of melanoma progression. CDR1as depletion results from epigenetic silencing of LINC00632, its originating long non-coding RNA (lncRNA) and promotes invasion in vitro and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as le…
Rational Combination of Parvovirus H1 With CTLA-4 and PD-1 Checkpoint Inhibitors Dampens the Tumor Induced Immune Silencing
2019
The recent therapeutic success of immune checkpoint inhibitors in the treatment of advanced melanoma highlights the potential of cancer immunotherapy. Oncolytic virus-based therapies may further improve the outcome of these cancer patients. A human ex vivo melanoma model was used to investigate the oncolytic parvovirus H-1 (H-1PV) in combination with ipilimumab and/or nivolumab. The effect of this combination on activation of human T lymphocytes was demonstrated. Expression of CTLA-4, PD-1, and PD-L1 immune checkpoint proteins was upregulated in H-1PV-infected melanoma cells. Nevertheless, maturation of antigen presenting cells such as dendritic cells was triggered by H-1PV infected melanom…
COVID-19: High-JAKing of the Inflammatory “Flight” by Ruxolitinib to Avoid the Cytokine Storm
2021
Since SARS-CoV-2 outbreak in December 2019, world health-system has been severely impacted with increased hospitalization, Intensive-Care-Unit (ICU) access and high mortality rates, mostly due to severe acute respiratory failure and multi-organ failure. Excessive and uncontrolled release of proinflammatory cytokines (cytokine release/storm syndrome, CRS) have been linked to the development of these events. The recent advancements of immunotherapy for the treatment of hematologic and solid tumors shed light on many of the molecular mechanisms underlying this phenomenon, thus rendering desirable a multidisciplinary approach to improve COVID-19 patients’ outcome. Indeed, currently available th…
A g316a polymorphism in the ornithine decarboxylase gene promoter modulates mycn‐driven childhood neuroblastoma
2021
Simple Summary Neuroblastoma is a devasting childhood cancer in which multiple copies (amplification) of the cancer-causing gene MYCN strongly predict poor outcome. Neuroblastomas are reliant on high levels of cellular components called polyamines for their growth and malignant behavior, and the gene regulating polyamine synthesis is called ODC1. ODC1 is often coamplified with MYCN, and in fact is regulated by MYCN, and like MYCN is prognostic of poor outcome. Here we studied a naturally occurring genetic variant or polymorphism that occurs in the ODC1 gene, and used gene editing to demonstrate the functional importance of this variant in terms of ODC1 levels and growth of neuroblastoma cel…
Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance
2019
Abstract In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epith…
Differential distribution and enrichment of non-coding RNAs in exosomes from normal and Cancer-associated fibroblasts in colorectal cancer.
2018
Exosome production from cancer-associated fibroblasts seems to be an important driver of tumor progression. We report the first in-depth biotype characterization of ncRNAs, analyzed by Next Generation Sequencing and Bioinformatics, expressed in established primary human normal and cancer-associated fibroblasts (CAFs) from cancer and normal mucosa tissues from 9 colorectal cancer patients, and/or packaged in their derived exosomes. Differential representation and enrichment analyses based on these ncRNAs revealed a significant number of differences between the ncRNA content of exosomes and the expression patterns of the normal and cancer-associated fibroblast cells. ncRNA regulatory elements…
HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer
2021
Simple Summary It has been previously shown that activation of the MET receptor by its ligand, the hepatocyte growth factor (HGF), modulates the tumor-stroma cross-talk in models of pancreatic cancer. We now wish to cast light on the molecular mechanisms by which this ligand/receptor pair sustains the interaction between cancer cells and the tumor microenviroment. To this end, we compared data obtained by large-scale analysis of gene expression in pancreatic cancer cells grown in the presence of HGF versus cells grown in the presence of HGF and treated with specific inhibitors of HGF/MET signaling. By clustering differentially expressed genes according to functional groups, we identified ca…
Melanoma Lesions Independently Acquire T-cell Resistance during Metastatic Latency
2016
Abstract Melanoma often recurs after a latency period of several years, presenting a T cell–edited phenotype that reflects a role for CD8+ T cells in maintaining metastatic latency. Here, we report an investigation of a patient with multiple recurrent lesions, where poorly immunogenic melanoma phenotypes were found to evolve in the presence of autologous tumor antigen–specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. CD8+ T cell–resistant, HLA class I–negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed that HLA …
Integrative Metabolomic and Transcriptomic Analysis for the Study of Bladder Cancer
2019
Metabolism reprogramming is considered a hallmark of cancer. The study of bladder cancer (BC) metabolism could be the key to developing new strategies for diagnosis and therapy. This work aimed to identify tissue and urinary metabolic signatures as biomarkers of BC and get further insight into BC tumor biology through the study of gene-metabolite networks and the integration of metabolomics and transcriptomics data. BC and control tissue samples (n = 44) from the same patients were analyzed by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance and microarrays techniques. Besides, urinary profiling study (n = 35) was performed in the same patients to identify a metabolomic profi…