Jean-Jacques Diaz

Jean-Jacques Diaz
Cancer Research Center of Lyon | CRCL · Department of Information Flow in the Cancer Cell

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176
Publications
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Publications

Publications (176)
Article
Importance: Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy. Objective: To evaluate the safety and efficacy of vistusertib in combi...
Article
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Background A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. Methods H...
Article
Growing evidence exposes translation and its translational machinery as key players in establishing and maintaining physiological and pathological biological processes. Examining translation may not only provide new biological insight but also identify novel innovative therapeutic targets in several fields of biology, including that of epithelial-t...
Article
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We previously showed that N6L, a pseudopeptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease in glob...
Article
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DHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here, we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in po...
Article
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Recent findings suggest that ribosomes, the translational machineries, can display a distinct composition depending on physio-pathological contexts. Thanks to outstanding technological breakthroughs, many studies have reported that variations of rRNA modifications, and more particularly the most abundant rRNA chemical modification, the rRNA 2′O-rib...
Article
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5-Fluorouracil (5-FU) is a chemotherapeutic drug widely used to treat patients with solid tumours, such as colorectal and pancreatic cancers. Colorectal cancer (CRC) is the second leading cause of cancer-related death and half of patients experience tumour recurrence. Used for over 60 years, 5-FU was long thought to exert its cytotoxic effects by a...
Article
5507 Background: Endometrial carcinoma is generally hormone dependent and aromatase inhibitors are used in routine practice before or after 1 st line chemotherapy (CT) for HR positive patients. Deregulation of the Pi3K-Akt-mTOR signaling pathway is observed in many tumor types including endometroid carcinoma driven oncogenesis and hormonal resistan...
Article
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Keratin 8 (K8) expressed at the surface of cancer cells, referred as externalized K8 (eK8), has been observed in a variety of carcinoma cell lines. K8 has been previously reported to be expressed in poorly differentiated head and neck squamous cell carcinoma (HNSCC); however, its role during the invasive phase of upper aerodigestive tract tumorigen...
Article
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Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in...
Article
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Recent epitranscriptomics studies unravelled that ribosomal RNA (rRNA) 2′O-methylation is an additional layer of gene expression regulation highlighting the ribosome as a novel actor of translation control. However, this major finding lies on evidences coming mainly, if not exclusively, from cellular models. Using the innovative next-generation Rib...
Article
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Many studies have focused on understanding the regulation and functions of aberrant protein synthesis in colorectal cancer (CRC), leaving the ribosome, its main effector, relatively underappreciated in CRC. The production of functional ribosomes is initiated in the nucleolus, requires coordinated ribosomal RNA (rRNA) processing and ribosomal protei...
Article
The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome bi...
Preprint
DHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in pol...
Preprint
Full-text available
Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stem...
Article
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BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously sho...
Article
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5-Fluorouracil (5-FU) is an anticancer drug extensively used for different cancers. Intracellular metabolic activation leads to several nucleoside and nucleotide metabolites essential to exert its cytotoxic activity on multiple cellular targets such as enzymes, DNA and RNA. In this paper, we describe the development of a method based on liquid chro...
Article
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Small nucleolar RNAs (snoRNAs) are non-coding RNAs localized in the nucleolus, where they participate in the cleavage and chemical modification of ribosomal RNAs. Their biogenesis and molecular functions have been extensively studied since their identification in the 1960s. However, their role in cancer has only recently started to emerge. In lung...
Article
High dietary iron intake is a risk factor for the development of colorectal cancer. However, how iron subsequently impacts the proliferation of colorectal cancer cells remains unclear. This study determined the expression of six iron regulatory genes in twenty-one human colorectal cancer (CRC) biopsies and matched normal colonic tissue. The results...
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Background: Dysregulation of ribosome biogenesis and alteration of ribosome composition, including alteration in ribosomal RNA (rRNA) 2'-O-ribose methylation, can play a role in malignant transformation and cancer progression. Several studies recently reported that components of the rRNA methylation complex are associated with leukemogenesis. Howe...
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Direct stochastic optical reconstruction microscopy (dSTORM), developed in the last decade, has revolutionised optical microscopy by enabling scientists to visualise objects beyond the resolution provided by conventional microscopy (200 nm). We developed an innovative method based on blinking particle standards and conditions for long-lived imaging...
Article
G-rich oligonucleotide, AS1411, has been shown to interact with nucleolin and to inhibit cancer cell proliferation and tumor growth. This antiproliferative action is increased when AS1411 is conjugated to different types of nanoparticles. However, the molecular mechanisms are not known. In this work, we show in several cell lines that optimized AS1...
Article
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Translation is one of the final steps that regulate gene expression. The ribosome is the effector of translation through to its role in mRNA decoding and protein synthesis. Many mechanisms have been extensively described accounting for translational regulation. However it emerged only recently that ribosomes themselves could contribute to this regu...
Article
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The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. A substantial fraction of the immunopeptidome derives from rapidly degraded nascent polypeptides (DRiPs). By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein ex...
Preprint
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The majority of inherited bone marrow failure (iBMF) syndromes are associated to nucleolar and/or ribosomal abnormalities, but Fanconi anemia (FA), the most common iBMF, is attributed to alterations in DNA damage responses. However, the involvement, if any, of the FA (FANC) proteins in the maintenance of nucleolar functions and/or ribosome biogenes...
Article
Full-text available
Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which...
Article
Ribosomes are nanomachines essential for protein production in all living cells. Ribosome synthesis increases in cancer cells to cope with a rise in protein synthesis and sustain unrestricted growth. This increase in ribosome biogenesis is reflected by severe morphological alterations of the nucleolus, the cell compartment where the initial steps o...
Article
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Ribosomal RNA (rRNA) undergoes post-transcriptional modification of over 200 nucleotides, predominantly 2′-O-methylation (2′-O-Me). 2′-O-Methylation protects RNA from hydrolysis and modifies RNA strand flexibility but does not contribute to Watson-Crick base pairing. The contribution of 2′-O-Me to the translational capacity of ribosomes has been es...
Article
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Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and transla...
Conference Paper
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Introduction Metastasis of cancer cells, a primary cause of cancer death and a multiple and intricate processes, may complicate the clinical management and lead to a poor prognosis for cancer patients and has tremendous physical or economic impact to patients or communities. Pentraxin 3 (PTX3) plays an important role in innate immune responses and...
Article
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Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, it rapidly came into light that p53 regulates gene expression to control...
Article
Full-text available
Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2'-O-methylation (2'-O-Me) is the most abundant rRNA chemical modification, and displays a complex pattern in rRNA. 2'-O-Me was shown to be essential for accurate and efficient protein synthesis in euk...
Article
Full-text available
MultiCellular Tumor Spheroids (MCTS), which mimic the 3-Dimensional (3D) organization of a tumor, are considered as better models than conventional cultures in 2-Dimensions (2D) to study cancer cell biology and to evaluate the response to chemotherapeutic drugs. A real time and quantitative follow-up of MCTS with simple and robust readouts to evalu...
Data
Quantification of live (calcein) and dead (PI) cells in the outer cells layer of SW480 spheroids treated with 0, 2, 10 and 100 μM of 5-FU at day 2. Left: the disaggregated outer layer is composed of both live and dead cells (50–50%) at all 5-FU concentrations. Right: the number of dead cells in the outer layer increases gradually with the 5-FU conc...
Data
Spreading of the three CRC spheroids on a collagen type I film. (A-I) Typical images of MCTS taken with the transmission channel of the confocal for the three cell lines at initial time 0h (A, D, G), 24h (B,E,H) and 48h (C,F,I) after depositing the spheroid on the collagen film. The culture medium was not renewed and does not contain 5-FU. Scale ba...
Data
Spheroid relative diameter change between 24h (after transfer) and 32h for the two invasive CRC cell lines. (A) Relative diameter change as a function of the 5-FU concentration. The diameter is evaluated from the spheroid surface area A including the diffuse outer layer measurement as (4A/π1/2. Error bars represent SEM (n = 7–12 for each cell line)...
Article
Full-text available
The nucleolar proteins which link cell proliferation to ribosome biogenesis are regarded to be potentially oncogenic. Here, in order to examine the involvement of an evolutionary conserved nucleolar protein SURF6/Rrp14 in proliferation and ribosome biogenesis in mammalian cells, we established stably transfected mouse NIH/3T3 fibroblasts capable of...
Article
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Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective...
Article
Full-text available
5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug in colorectal cancer. Previous studies showed that 5-FU modulates RNA metabolism and mRNA expression. In addition, it has been reported that 5-FU incorporates into the RNAs constituting the translational machinery and that 5-FU affects the amount of some mRNAs associated with ribosomes. H...
Article
Full-text available
Acute myeloid leukemia (AML) is a heterogeneous disease. Prognosis is mainly influenced by patient age at diagnosis and cytogenetic alterations, two of the main factors currently used in AML patient risk stratification. However, additional criteria are required to improve the current risk classification and better adapt patient care. In neoplastic...
Data
Over-expression of NCL and Nop56 in AML patients. (A-B) Correlation between log2 (Relative mRNA levels) issued from two different sets of primers to analyze expression of NCL (A) and Nop56 (B). Correlation was determined using Spearman test. (C-H) Mean comparison of NCL and Nop56 gene expression between controls and AML patients using Mann-Whitey t...
Data
Expression and clinical data of human samples. (XLS)
Data
Comparison of expression of different internal reference genes for relative gene quantification using qPCR. Ct values of three internal reference genes, GAPDH (A), ACTB (B) and 18S (C), were compared to identify the most suitable housekeeping gene in our experimental conditions. Three major criteria were required: first, the absence of significant...
Data
C-Myc but not NPM1 is over-expressed in AML patients. (A) Validation of high-throughput qPCR method using microfluidic system device. Correlation between fold-changes calculated from Ct values determined by classical RT-qPCR and high-throughput qPCR was investigated on few samples for C-Myc and NPM1 gene using Spearman test. (B-C) Expression of C-M...
Data
Supporting File including Supporting Tables. (DOCX)
Data
Overall survival of AML patients related to NCL in intermediate group of cytogenetic risk classification in TCGA series. (A-B) Kaplan-Meier analysis of overall survival rates (event = death related to AML disease) according to cytogenetic risk classification (A) and to NCL in intermediate group of cytogenetic risk classification in AML patients (B)...
Data
Detection of nucleoli in cells of control and AML patient's bone marrow smears. Immunofluorescence staining of nucleolar FBL and NCL on control (top panel) and AML (bottom panel) patient's bone marrow smears. FBL (green) and NCL (red) pattern are shown individually in top and middle images, and merged image with nuclei staining (blue) is shown in t...
Data
Increased number and size of nucleoli in AML patient’s bone marrow smears. (A) Quantification and analysis of nucleoli number by image analysis from 4 control and 6 AML bone marrow smears. The number of nucleoli per cell was measured using FBL signal in each samples and ranged from 0 to 4. The median number of nucleoli per cell was represented for...
Data
Expression distribution of markers of ribosome biogenesis in AML patients. (A) Expression distribution of the different genes analyzed by high-throughput qPCR in series 3. (B) Expression distribution of the different genes analyzed by RNA-seq in series TCGA. Box and whisker plots represent median (middle bar in the box), interquartile range (bottom...
Article
Ribosome biogenesis is the process of synthesis of the cellular ribosomes which mediate protein translation. Integral with the ribosomes are four cytoplasmic ribosomal RNAs (rRNAs) which show extensive post-transcriptional modifications including 2′-O-methylation and pseudouridylation. Several hereditary hematologic diseases including Diamond-Black...
Article
Accumulating evidence suggests the unusual presence of proteins at the external leaflet of plasma membrane of cancer cells while, in normal cells, these proteins are expressed in the intracellular compartments. They lack transmembrane domains and signal sequences that allow delivery to the plasma membrane and their role is not fully understood. As...
Article
Full-text available
Influenza viruses replicate their single-stranded RNA genomes in the nucleus of infected cells and these replicated genomes (vRNPs) are then exported from the nucleus to the cytoplasm and plasma membrane before budding. To achieve this export, influenza viruses hijack the host cell export machinery. However, the complete mechanisms underlying this...
Article
The expression of Wingless and Int-related proteins (Wnt) ligands is aberrantly high in human breast cancer. We report here that WNT4 is significantly upregulated at the mRNA and protein level in mammary carcinoma cells expressing autocrine human growth hormone (hGH). Depletion of WNT4 using small-interfering (si) RNA markedly decreased the rate of...
Chapter
RNAs are intrinsic components of the translational apparatus, rRNA, tRNA, and mRNA. For many years it has been accepted that translational regulation proceeds via mRNA cis-regulatory elements and protein factors. Recently, trans-acting regulatory factors made of RNA have been identified as major regulators of translation. RNAs are mainly composed o...