Genetic aberrations, including chromosomal rearrangements, loss or amplification of DNA, and point mutations, are major elements of cancer development ....
Pancreatic cancer stem cells (PaCSCs) drive pancreatic cancer tumorigenesis, chemoresistance and metastasis. While eliminating this subpopulation of cells would theoretically result in tumor ...eradication, PaCSCs are extremely plastic and can successfully adapt to targeted therapies. In this study, we demonstrate that PaCSCs increase expression of interferon-stimulated gene 15 (ISG15) and protein ISGylation, which are essential for maintaining their metabolic plasticity. CRISPR-mediated ISG15 genomic editing reduces overall ISGylation, impairing PaCSCs self-renewal and their in vivo tumorigenic capacity. At the molecular level, ISG15 loss results in decreased mitochondrial ISGylation concomitant with increased accumulation of dysfunctional mitochondria, reduced oxidative phosphorylation (OXPHOS) and impaired mitophagy. Importantly, disruption in mitochondrial metabolism affects PaCSC metabolic plasticity, making them susceptible to prolonged inhibition with metformin in vivo. Thus, ISGylation is critical for optimal and efficient OXPHOS by ensuring the recycling of dysfunctional mitochondria, and when absent, a dysregulation in mitophagy occurs that negatively impacts PaCSC stemness.
Gastrointestinal (GI) cancers are malignancies that develop within the digestive system and account for one in four cancer cases according to WHO data ....
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 are specifically packaged in CAF-derived exosomes, supporting a specific cross-talk between CAFs and colon cancer cells and/or other stromal cells, mediated by exosomes. These sncRNAs are potential biomarkers present in cancer-associated fibroblast-derived exosomes, which should thereby contribute to developing new non-invasive diagnostic, prognostic and predictive methods for clinical applications in management of cancer patients.
Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely ...one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O
) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers worldwide, primarily due to its robust desmoplastic stroma and immunosuppressive tumor microenvironment (TME), which facilitate ...tumor progression and metastasis. In addition, fibrous tissue leads to sparse vasculature, high interstitial fluid pressure, and hypoxia, thereby hindering effective systemic drug delivery and immune cell infiltration. Thus, remodeling the TME to enhance tumor perfusion, increase drug retention, and reverse immunosuppression has become a key therapeutic strategy. In recent years, targeting epigenetic pathways has emerged as a promising approach to overcome tumor immunosuppression and cancer progression. Moreover, the progress in nanotechnology has provided new opportunities for enhancing the efficacy of conventional and epigenetic drugs. Nano-based drug delivery systems (NDDSs) offer several advantages, including improved drug pharmacokinetics, enhanced tumor penetration, and reduced systemic toxicity. Smart NDDSs enable precise targeting of stromal components and augment the effectiveness of immunotherapy through multiple drug delivery options. This review offers an overview of the latest nano-based approaches developed to achieve superior therapeutic efficacy and overcome drug resistance. We specifically focus on the TME and epigenetic-targeted therapies in the context of PDAC, discussing the advantages and limitations of current strategies while highlighting promising new developments. By emphasizing the immense potential of NDDSs in improving therapeutic outcomes in PDAC, our review paves the way for future research in this rapidly evolving field.
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•Specific PDAC tumor microenvironment features contribute to its poor prognosis.•Targeting epigenetic pathways holds the potential for overcoming immunosuppression.•Nano-based drug delivery systems provide enhanced therapeutic capabilities.•These strategies show promise for stroma remodeling and better therapeutic response.•Future research in this evolving field paves the way for improved patient outcomes.
3D bioprinting involves using bioinks that combine biological and synthetic materials. The selection of the most appropriate cell-material combination for a specific application is complex, and there ...is a lack of consensus on the optimal conditions required. Plasma-loaded alginate and alginate/methylcellulose (Alg/MC) inks were chosen to study their viscoelastic behaviour, degree of recovery, gelation kinetics, and cell survival after printing. Selected inks showed a shear thinning behavior from shear rates as low as 0.2 s
and the ink composed of 3%
SA and 9%
MC was the only one showing a successful stacking and 96% recovery capacity. A 0.5 × 10
PANC-1 cell-laden bioink was extruded with an Inkredible 3D printer (Cellink) through a D = 410 μm tip conical nozzle into 6-well culture plates. Cylindrical constructs were printed and crosslinked with CaCl
. Bioinks suffered a 1.845 Pa maximum pressure at the tip that was not deleterious for cellular viability. Cell aggregates can be appreciated for the cut total length observed in confocal microscopy, indicating a good proliferation rate at different heights of the construct, and suggesting the viability of the selected bioink PANC-1/P-Alg
/MC
for building up three-dimensional bioprinted pancreatic tumor constructs.
Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) ...are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. Despite the occurrence of oncogenic mutations and the evidence for downstream ERK/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin.
Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood ...stream. Here we explore the use of sAXL as a biomarker for PDAC.
AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models.
AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours.
sAXL appears as a biomarker for early detection of PDAC and PDAC–CP discrimination that could accelerate treatment and improve its dismal prognosis.
This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya.
Ultrasounds (US) are a non-ionizing mechanical wave, with less adverse effects than conventional pharmacological or surgical treatments. Different biological effects are induced in tissues and cells ...by ultrasound actuation depending on acoustic parameters, such as the wave intensity, frequency and treatment dose. This non-ionizing radiation has considerable applications in biomedicine including surgery, medical imaging, physical therapy and cancer therapy. Depending on the wave intensity, US are applied as high-intensity ultrasounds (HIUS) and low-intensity pulsed ultrasounds (LIPUS), with different effects on cells and tissues. HIUS produce thermal and mechanical effects, resulting in a large localized temperature increase, leading to tissue ablation and even tumor necrosis. This can be achieved by focusing low intensity waves emitted from different electrically shifted transducers, known as high-intensity focused ultrasounds (HIFU). LIPUS have been used extensively as a therapeutic, surgical and diagnostic tool, with diverse biological effects observed in tissues and cultured cells. US represent a non-invasive treatment strategy that can be applied to selected areas of the body, with limited adverse effects. In fact, tumor ablation using HIFU has been used as a curative treatment in patients with an early-stage pancreatic tumor and is an effective palliative treatment in patients with advanced stage disease. However, the biological effects, dose standardization, benefit-risk ratio and safety are not fully understood. Thus, it is an emerging field that requires further research in order to reach its full potential.
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