Proteomic and Genomic Signatures of Repeat-instability in Cancer and Adjacent Normal Tissues

SummaryRepetitive sequences are hotspots of evolution at multiple levels. However, due to technical difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content of proteomes and genomes, directly from proteomic and genomic raw sequence data, and applied it to analyze a wide range of tumors and normal tissues. We identify high similarity between the repeat-instability in tumors and their patient-matched normal tissues, but also tumor-specific signatures, both in protein expression and in the genome, that strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We find an inverse relationship between repeat-instability and point mutation load, within and across patients, and independently of other somatic aberrations. Thus, repeat-instability is a distinct, transient and compensatory adaptive mechanism in tumor evolution.

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Proteomic and genomic signatures of repeat instability in cancer and adjacent normal tissues

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1908790116 ◽

2019 ◽

Vol 116 (34) ◽

pp. 16987-16996 ◽

Cited By ~ 4

Author(s):

Erez Persi ◽

Davide Prandi ◽

Yuri I. Wolf ◽

Yair Pozniak ◽

Georgina D. Barnabas ◽

...

Keyword(s):

Cancer Progression ◽

Repetitive Sequences ◽

Tumor Evolution ◽

Repeat Instability ◽

Primary Tumors ◽

Normal Tissues ◽

Genomic Signatures ◽

Repeat Content ◽

Wide Range

Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in proteomes and genomes directly from proteomic and genomic raw data. This method was applied to a wide range of tumors and normal tissues. We identify high similarity between repeat instability patterns in tumors and their patient-matched adjacent normal tissues. Nonetheless, tumor-specific signatures both in protein expression and in the genome strongly correlate with cancer progression and robustly predict the tumorigenic state. In a patient, the hierarchy of genomic repeat instability signatures accurately reconstructs tumor evolution, with primary tumors differentiated from metastases. We observe an inverse relationship between repeat instability and point mutation load within and across patients independent of other somatic aberrations. Thus, repeat instability is a distinct, transient, and compensatory adaptive mechanism in tumor evolution and a potential signal for early detection.

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OncoGEMINI: software for investigating tumor variants from multiple biopsies with integrated cancer annotations

Genome Medicine ◽

10.1186/s13073-021-00854-6 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Thomas J. Nicholas ◽

Michael J. Cormier ◽

Xiaomeng Huang ◽

Yi Qiao ◽

Gabor T. Marth ◽

...

Keyword(s):

Sequence Data ◽

Sampling Time ◽

Tumor Evolution ◽

Significant Challenge ◽

Multiple Biopsies ◽

Wide Range ◽

Cancer Mutations ◽

Cancer Types ◽

Multiple Samples ◽

Tumor Sampling

Abstract Background DNA sequencing has unveiled extensive tumor heterogeneity in several different cancer types, with many exhibiting diverse subclonal populations. Identifying and tracing mutations throughout the expansion and progression of a tumor represents a significant challenge. Furthermore, prioritizing the subset of such mutations most likely to contribute to tumor evolution or that could serve as potential therapeutic targets represents an ongoing problem. Results Here, we describe OncoGEMINI, a new tool designed for exploring the complex patterns and trajectory of somatic and inherited variation observed in heterogeneous tumors biopsied over the course of treatment. This is accomplished by creating a searchable database of variants that includes tumor sampling time points and allows for filtering methods that reflect specific changes in variant allele frequencies over time. Additionally, by incorporating existing annotations and resources that facilitate the interpretation of cancer mutations (e.g., CIViC, DGIdb), OncoGEMINI enables rapid searches for, and potential identification of, mutations that may be driving subclonal evolution. Conclusions By combining relevant genomic annotations alongside specific filtering tools, OncoGEMINI provides powerful and customizable approaches that enable the quick identification of individual tumor variants that meet specified criteria. It can be applied to a wide range of tumor-derived sequence data, but is especially designed for studies with multiple samples, including longitudinal datasets. It is available under an MIT license at github.com/fakedrtom/oncogemini.

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Downregulation of CacyBP by CRISPR/dCas9-KRAB Prevents Bladder Cancer Progression

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.692941 ◽

2021 ◽

Vol 8 ◽

Author(s):

Hanxiong Zheng ◽

Chiheng Chen

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Scratch Assay ◽

Binding Partner ◽

Normal Tissues ◽

Cellular Processes ◽

Protein Ubiquitination ◽

Wide Range ◽

Cytoskeletal Dynamics ◽

And Migration

Bladder cancer (BCa) is a leading cause of cancer-related death in the world. CacyBP is initially described as a binding partner of calcyclin and has been shown to be involved in a wide range of cellular processes, including cell differentiation, proliferation, protein ubiquitination, cytoskeletal dynamics and tumorigenesis. In the present study, we found that CacyBP expression was significantly upregulated in BCa tissues compared with adjacent normal tissues. Moreover, its expression was negatively correlated with overall survival time. Secondly, CacyBP had higher expressions in BCa cell lines than normal urothelial cells which was consistent with the results of BCa tissues. Finally, knockdown of CacyBP by CRIPSR-dCas9-KRAB in T24 and 5,637 BCa cells inhibited cell proliferation and migration by CCK-8 assay and scratch assay, and promoted apoptosis by caspase-3/ELISA. These data elucidate that CacyBP is an important oncogene contributing to malignant behavior of BCa and provide a potentially molecular target for treatment of BCa.

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mtDNAcombine: tools to combine sequences from multiple studies

BMC Bioinformatics ◽

10.1186/s12859-021-04048-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Eleanor F. Miller ◽

Andrea Manica

Keyword(s):

Sequence Data ◽

Data Extraction ◽

Bayesian Skyline Plot ◽

Model Organisms ◽

Data Sets ◽

Data Handling ◽

Online Database ◽

Genetic Studies ◽

Wide Range ◽

Existing Data

Abstract Background Today an unprecedented amount of genetic sequence data is stored in publicly available repositories. For decades now, mitochondrial DNA (mtDNA) has been the workhorse of genetic studies, and as a result, there is a large volume of mtDNA data available in these repositories for a wide range of species. Indeed, whilst whole genome sequencing is an exciting prospect for the future, for most non-model organisms’ classical markers such as mtDNA remain widely used. By compiling existing data from multiple original studies, it is possible to build powerful new datasets capable of exploring many questions in ecology, evolution and conservation biology. One key question that these data can help inform is what happened in a species’ demographic past. However, compiling data in this manner is not trivial, there are many complexities associated with data extraction, data quality and data handling. Results Here we present the mtDNAcombine package, a collection of tools developed to manage some of the major decisions associated with handling multi-study sequence data with a particular focus on preparing sequence data for Bayesian skyline plot demographic reconstructions. Conclusions There is now more genetic information available than ever before and large meta-data sets offer great opportunities to explore new and exciting avenues of research. However, compiling multi-study datasets still remains a technically challenging prospect. The mtDNAcombine package provides a pipeline to streamline the process of downloading, curating, and analysing sequence data, guiding the process of compiling data sets from the online database GenBank.

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Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers

Cancers ◽

10.3390/cancers13010068 ◽

2020 ◽

Vol 13 (1) ◽

pp. 68

Author(s):

Fulvio Massaro ◽

Florent Corrillon ◽

Basile Stamatopoulos ◽

Nathalie Meuleman ◽

Laurence Lagneaux ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Progression ◽

Cancer Progression ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Cell Communication ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Wide Range ◽

Major Player

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

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Mitochondria-Targeted Antioxidants MitoQ and MitoTEMPO Do Not Influence BRAF-Driven Malignant Melanoma and KRAS-Driven Lung Cancer Progression in Mice

Antioxidants ◽

10.3390/antiox10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Kristell Le Gal ◽

Clotilde Wiel ◽

Mohamed X. Ibrahim ◽

Marcus Henricsson ◽

Volkan I. Sayin ◽

...

Keyword(s):

Lung Cancer ◽

Malignant Melanoma ◽

Cancer Cells ◽

Cancer Progression ◽

Nuclear Dna ◽

Human Melanoma ◽

Oxygen Species ◽

Lung Cancer Cell ◽

Primary Tumors ◽

Anti Cancer

Cancer cells produce high levels of mitochondria-associated reactive oxygen species (ROS) that can damage macromolecules, but also promote cell signaling and proliferation. Therefore, mitochondria-targeted antioxidants have been suggested to be useful in anti-cancer therapy, but no studies have convincingly addressed this question. Here, we administered the mitochondria-targeted antioxidants MitoQ and MitoTEMPO to mice with BRAF-induced malignant melanoma and KRAS-induced lung cancer, and found that these compounds had no impact on the number of primary tumors and metastases; and did not influence mitochondrial and nuclear DNA damage levels. Moreover, MitoQ and MitoTEMPO did not influence proliferation of human melanoma and lung cancer cell lines. MitoQ and its control substance dTPP, but not MitoTEMPO, increased glycolytic rates and reduced respiration in melanoma cells; whereas only dTPP produced this effect in lung cancer cells. Our results do not support the use of mitochondria-targeted antioxidants for anti-cancer monotherapy, at least not in malignant melanoma and lung cancer.

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Synthesis and characterization of a new series of thiadiazole derivatives as potential anticancer agents

Heterocyclic Communications ◽

10.1515/hc-2020-0002 ◽

2020 ◽

Vol 26 (1) ◽

pp. 6-13 ◽

Cited By ~ 1

Author(s):

Ulviye Acar Çevik ◽

Derya Osmaniye ◽

Serkan Levent ◽

Begüm Nurpelin Sağlik ◽

Betül Kaya Çavuşoğlu ◽

...

Keyword(s):

Anticancer Agents ◽

Biological Activities ◽

Cancer Cell Line ◽

Chemotherapeutic Agents ◽

Anticancer Activities ◽

Normal Tissues ◽

H Nmr ◽

Wide Range ◽

Thiadiazole Derivatives ◽

Low Efficiency

AbstractCancer is one of the most common causes of death in the world. Despite the importance of combating cancer in healthcare systems and research centers, toxicity in normal tissues and the low efficiency of anticancer drugs are major problems in chemotherapy. Nowadays the aim of many medical research projects is to discover new safer and more effective anticancer agents. 1,3,4-Thiadiazole compounds are important fragments in medicinal chemistry because of their wide range of biological activities, including anticancer activities. The aim of this study was to determine the capacity of newly synthesized 1,3,4-thiadiazole compounds as chemotherapeutic agents. The structures of the obtained compounds were elucidated using 1H-NMR, 13C-NMR and mass spectrometry. Although the thiadiazole derivatives did not prove to be significantly cytotoxic to the tumour tissue cultures, compound 4i showed activity against the C6 rat brain cancer cell line (IC50 0.097 mM) at the tested concentrations.

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Sequence data from isolated lichen-associated melanized fungi enhance delimitation of two new lineages within Chaetothyriomycetidae

Mycological Progress ◽

10.1007/s11557-021-01706-8 ◽

2021 ◽

Vol 20 (7) ◽

pp. 911-927

Author(s):

Lucia Muggia ◽

Yu Quan ◽

Cécile Gueidan ◽

Abdullah M. S. Al-Hatmi ◽

Martin Grube ◽

...

Keyword(s):

Sequence Data ◽

Single Species ◽

Sister Group ◽

Asexual Propagation ◽

Dna Sequence Data ◽

Wide Range ◽

The Family ◽

Rock Inhabiting Fungi ◽

Stable Habitat

AbstractLichen thalli provide a long-lived and stable habitat for colonization by a wide range of microorganisms. Increased interest in these lichen-associated microbial communities has revealed an impressive diversity of fungi, including several novel lineages which still await formal taxonomic recognition. Among these, members of the Eurotiomycetes and Dothideomycetes usually occur asymptomatically in the lichen thalli, even if they share ancestry with fungi that may be parasitic on their host. Mycelia of the isolates are characterized by melanized cell walls and the fungi display exclusively asexual propagation. Their taxonomic placement requires, therefore, the use of DNA sequence data. Here, we consider recently published sequence data from lichen-associated fungi and characterize and formally describe two new, individually monophyletic lineages at family, genus, and species levels. The Pleostigmataceae fam. nov. and Melanina gen. nov. both comprise rock-inhabiting fungi that associate with epilithic, crust-forming lichens in subalpine habitats. The phylogenetic placement and the monophyly of Pleostigmataceae lack statistical support, but the family was resolved as sister to the order Verrucariales. This family comprises the species Pleostigma alpinum sp. nov., P. frigidum sp. nov., P. jungermannicola, and P. lichenophilum sp. nov. The placement of the genus Melanina is supported as a lineage within the Chaetothyriales. To date, this genus comprises the single species M. gunde-cimermaniae sp. nov. and forms a sister group to a large lineage including Herpotrichiellaceae, Chaetothyriaceae, Cyphellophoraceae, and Trichomeriaceae. The new phylogenetic analysis of the subclass Chaetothyiomycetidae provides new insight into genus and family level delimitation and classification of this ecologically diverse group of fungi.

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The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-01849-2 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Mingyi Zhou ◽

Zhuo Yang ◽

Danbo Wang ◽

Peng Chen ◽

Yong Zhang

Keyword(s):

Cervical Cancer ◽

Cancer Progression ◽

Cell Cycle Progression ◽

Critical Role ◽

Circular Rna ◽

Circular Rnas ◽

Cyclin E1 ◽

Normal Tissues ◽

Exact Function ◽

Potential Biomarker

Abstract Background As a novel type of non-coding RNA, circular RNAs (circRNAs) play a critical role in the initiation and development of various diseases, including cancer. However, the exact function of circRNAs in human cervical cancer remains largely unknown. Methods We identified the circRNA signature of upregulated circRNAs between cervical cancer and paired adjacent normal tissues. Using two different cohorts and GEO database, a total of six upregulated circRNAs were identified with a fold change > 2, and P < 0.05. Among these six circRNAs, hsa_circ_0072088 (circZFR) was the only exonic circRNA significantly overexpressed in cervical cancer. Functional experiments were performed to investigate the biological function of circZFR. CircRNA pull-down, circRNA immunoprecipitation (circRIP) and Co-immunoprecipitation (Co-IP) assays were executed to investigate the molecular mechanism underlying the function of circZFR. Results Functionally, circZFR knockdown represses the proliferation, invasion, and tumor growth. Furthermore, circRNA pull-down experiments combined with mass spectrometry unveil the interactions of circZFR with Single-Stranded DNA Binding Protein 1 (SSBP1). Mechanistically, circZFR bound with SSBP1, thereby promoting the assembly of CDK2/cyclin E1 complexes. The activation of CDK2/cyclin E1 complexes induced p-Rb phosphorylation, thus releasing activated E2F1 leading to cell cycle progression and cell proliferation. Conclusion Our findings provide the first evidence that circZFR is a novel onco-circRNA and might be a potential biomarker and therapeutic target for cervical cancer patients.

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