In cancer research, the term epigenetics was used in the 1970s in its modern sense encompassing non-genetic events modifying the chromatin state, mainly to oppose the emerging oncogene paradigm. However, starting from the establishment of this prominent concept, the importance of these epigenetic phenomena in cancer rarely led to questioning the causal role of genetic alterations. Only in the last 10 years, the accumulation of problematic data, better experimental technologies, and some ambitious models pushed the idea that epigenetics could be at least as important as genetics in early oncogenesis.
View Article and Find Full Text PDFBackground: Lung cancer is the leading cause of cancer death worldwide, with poor survival despite recent therapeutic advances. A better understanding of the complexity of the tumor microenvironment is needed to improve patients' outcome.
Methods: We applied a computational immunology approach (involving immune cell proportion estimation by deconvolution, transcription factor activity inference, pathways and immune scores estimations) in order to characterize bulk transcriptomics of 62 primary lung adenocarcinoma (LUAD) samples from patients across disease stages.
Cancer cells are highly plastic, allowing them to adapt to changing conditions. Genes related to basic cellular processes evolved in ancient species, while more specialized genes appeared later with multicellularity (metazoan genes) or even after mammals evolved. Transcriptomic analyses have shown that ancient genes are up-regulated in cancer, while metazoan-origin genes are inactivated.
View Article and Find Full Text PDFIntroduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation.
View Article and Find Full Text PDFUnlabelled: Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA syntheses and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication.
View Article and Find Full Text PDFIn mammals, insulators contribute to the regulation of loop extrusion to organize chromatin into topologically associating domains. In Drosophila the role of insulators in 3D genome organization is, however, under current debate. Here, we addressed this question by combining bioinformatics analysis and multiplexed chromatin imaging.
View Article and Find Full Text PDFPLoS Comput Biol
August 2023
Inference of gene regulatory networks has been an active area of research for around 20 years, leading to the development of sophisticated inference algorithms based on a variety of assumptions and approaches. With the ever increasing demand for more accurate and powerful models, the inference problem remains of broad scientific interest. The abstract representation of biological systems through gene regulatory networks represents a powerful method to study such systems, encoding different amounts and types of information.
View Article and Find Full Text PDFUnlabelled: Lung adenocarcinoma (LUAD) is a heterogeneous group of tumors associated with different survival rates, even when detected at an early stage. Here, we aim to investigate the biological determinants of early LUAD indolence or aggressiveness using radiomics as a surrogate of behavior. We present a set of 92 patients with LUAD with data collected across different methodologies.
View Article and Find Full Text PDFMonocyte-derived macrophages help maintain tissue homeostasis and defend the organism against pathogens. In tumors, recent studies have uncovered complex macrophage populations, including tumor-associated macrophages, which support tumorigenesis through cancer hallmarks such as immunosuppression, angiogenesis, or matrix remodeling. In the case of chronic lymphocytic leukemia, these macrophages are known as nurse-like cells (NLCs) and they protect leukemic cells from spontaneous apoptosis, contributing to their chemoresistance.
View Article and Find Full Text PDFIncreasing numbers of datasets and experimental assays that capture the organization of chromatin inside the nucleus warrant an effort to develop tools to visualize and analyze these structures. Alongside polymer physics or constraint-based modeling, network theory approaches to describe 3D epigenome organization have gained in popularity. Representing genomic regions as nodes in a network enables visualization of 1D epigenomics datasets in the context of chromatin structure maps, while network theory metrics can be used to describe 3D epigenome organization and dynamics.
View Article and Find Full Text PDFSpatially resolved omics enable the discovery of tissue organization of biological or clinical importance. Despite the existence of several methods, performing a rational analysis including multiple algorithms while integrating different conditions such as clinical data is still not trivial. To make such investigations more accessible, we developed , a Python package to analyze spatial omics data with respect to clinical or biological data and to gain insight on cell interaction patterns or tissue architecture of biological relevance.
View Article and Find Full Text PDFIn mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled. Replicative stress triggers additional initiation events from 'dormant' origins whose genomic distribution and regulation are not well understood. In this study, we have analyzed origin activity in mouse embryonic stem cells in the absence or presence of mild replicative stress induced by aphidicolin, a DNA polymerase inhibitor, or by deregulation of origin licensing factor CDC6.
View Article and Find Full Text PDFBackground: The molecular pathogenesis of T-cell large granular lymphocytic leukemia (T-LGLL), a mature T-cell leukemia arising commonly from T-cell receptor αβ-positive CD8 memory cytotoxic T cells, is only partly understood. The role of deregulated methylation in T-LGLL is not well known. We analyzed the epigenetic profile of T-LGLL cells of 11 patients compared to their normal counterparts by array-based DNA methylation profiling.
View Article and Find Full Text PDFFront Bioinform
October 2021
Recent technological advances have allowed us to map chromatin conformation and uncover the genome's spatial organization of the genome inside the nucleus. These experiments have revealed the complexities of genome folding, characterized by the presence of loops and domains at different scales, which can change across development and in different cell types. There is strong evidence for a relationship between the topological properties of chromatin contacts and cellular phenotype.
View Article and Find Full Text PDFCohesin exists in two variants containing STAG1 or STAG2. STAG2 is one of the most mutated genes in cancer and a major bladder tumor suppressor. Little is known about how its inactivation contributes to tumorigenesis.
View Article and Find Full Text PDFBioinformatics
November 2021
Summary: Networks provide a powerful framework to analyze spatial omics experiments. However, we lack tools that integrate several methods to easily reconstruct networks for further analyses with dedicated libraries. In addition, choosing the appropriate method and parameters can be challenging.
View Article and Find Full Text PDFDNA replication timing (RT), reflecting the temporal order of origin activation, is known as a robust and conserved cell-type specific process. Upon low replication stress, the slowing of replication forks induces well-documented RT delays associated to genetic instability, but it can also generate RT advances that are still uncharacterized. In order to characterize these advanced initiation events, we monitored the whole genome RT from six independent human cell lines treated with low doses of aphidicolin.
View Article and Find Full Text PDFMutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells.
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