Miguel Godinho Ferreira

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Verified

Miguel verified their affiliation via an institutional email.

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• Ph.D.
• Group Leader at French National Centre for Scientific Research

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and sen...

Fish telomere lengths vary significantly across the numerous species, implicating diverse life strategies and environmental adaptations. Zebrafish have telomere dynamics that are comparable to humans and are emerging as a key model in which to unravel the systemic effects of telomere shortening on aging and interorgan communication. Here, we discus...

Most cancers re-activate telomerase to maintain telomere length and thus acquire immortality. Activating telomerase promoter mutations are found in many cancers, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. We combined the telomerase mutant (tert−/−) with two established zebrafish mela...

Telomere shortening is a hallmark of aging and is counteracted by telomerase. As in humans, the zebrafish gut is one of the organs with the fastest rate of telomere decline, triggering early tissue dysfunction during normal zebrafish aging and in prematurely aged telomerase mutants. However, whether telomere-dependent aging of an individual organ,...

Telomeres shorten with each cell division and telomere dysfunction is a recognized hallmark of aging. Tissue proliferation is expected to dictate the rate at which telomeres shorten. We set out to test whether proliferative tissues age faster than non-proliferative due to telomere shortening during zebrafish aging. We performed a prospective study...

Telomerase activity is restricted in somatic cells, resulting in progressive telomere shortening. Telomere erosion eventually activates the DNA damage response (DDR), inducing cell-cycle arrest and cellular senescence or apoptosis. We previously reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) whic...

Chemotherapy remains the mainstay in most high-risk breast cancer (BC) settings, with several equivalent options of treatment. However, the efficacy of each treatment varies between patients and there is currently no test to determine which option will be the most effective for each individual patient. Here, we developed a fast in-vivo test for BC...

ZBTB48 (also known as TZAP) is a transcription factor that has previously been reported to bind to telomeres and act as a negative regulator of telomere length in human cell lines. To explore whether transcription factor activity and telomere length regulation are conserved at the organismal level in vertebrates, we generate a zbtb48−/− zebrafish l...

Chemotherapy remains the mainstay in most high-risk breast cancer (BC) settings, with several equivalent options of treatment. However, the efficacy of each treatment varies between patients and there is currently no test to determine which option will be the most effective for each individual patient. Here, we developed a fast in-vivo test for BC...

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type I interferon inflammation and senescenc...

Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic...

Telomere length, unlike most genetic traits, is epigenetic, in the sense that it is not fully coded by the genome. Telomeres vary in length and randomly assort to the progeny leaving some individuals with longer and others with shorter telomeres. Telomerase activity counteracts this by extending telomeres in the germline and during embryogenesis bu...

Telomeres are nucleoprotein comple x es that protect the chromosome-ends from eliciting DNA repair while ensuring their complete duplication. Pot1 is a subunit of telomere capping complex that binds to the G-rich o v erhang and inhibits the activation of DNA damage c hec kpoints. In this study, w e e xplore ne w functions of fission y east Pot1 b y...

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and...

Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 that result in apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic...

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and...

Most cancers reactivate telomerase to maintain telomere length to acquire immortality. The importance of this process is well illustrated by the fact that telomerase promoter mutations are found at a high frequency in many cancer types, including melanoma. However, it is unclear when and if telomerase is strictly required during tumorigenesis. Here...

Telomeres are nucleoprotein complexes that protect the chromosome-ends from eliciting DNA repair while ensuring their complete duplication. Pot1 is a subunit of telomere capping complex that binds to the G-rich overhang and inhibits the activation of DNA damage checkpoints. In this study, we explore new functions of fission yeast Pot1 by using a po...

Senescence-associated beta-galactosidase (SA-β-GAL) is an enzyme that accumulates in the lysosomes of senescent cells, where it hydrolyses β-galactosides. With p16, it represents a well-recognized biomarker used to assess senescence both in vivo and in cell culture. The use of a chromogenic substrate, such as 5-bromo-4-chloro-3-indoyl- β-d-galactop...

Telomere shortening is a hallmark of aging and is counteracted by telomerase. The gut is one of the earliest organs to exhibit short telomeres and tissue dysfunction during normal zebrafish aging. This is recapitulated in prematurely aged telomerase mutants (tert-/-). Here, we show that gut-specific telomerase activity in tert-/- zebrafish prevents...

Purpose Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to o...

From our own experience, we acknowledge that the SA-b-Gal assay contains critical steps that must be followed to ensure a proper staining of senescent cells. We have written a Bio-Protocol article in which we detail the procedures to perform SA-b-Gal staining on adult zebrafish (DOI: 10.21769/BioProtoc.4457).

Telomeres and telomerase prevent the continuous erosion of chromosome‐ends caused by lifelong cell division. Shortened telomeres are associated with age‐related pathologies. While short telomere length is positively correlated with increased lethality at the individual level, in comparisons across species short telomeres are associated with long (a...

The role of telomerase reverse transcriptase has been widely investigated in the contexts of ageing and age-related diseases. Interestingly, decreased telomerase activities (and accelerated telomere shortening) have also been reported in patients with emotion-related disorders, opening the possibility for subjective appraisal of stressful stimuli p...

Tumor models allowing for the in vivo investigation of molecular mechanisms driving tumor progression and metastasis are important to develop novel strategies for cancer treatment. Unfortunately, for Ewing sarcoma no adequate genetic animal models are currently available. Mouse xenograft models are the state of the art to model Ewing sarcoma in viv...

Telomere length is correlated positively with longevity at the individual level, but negatively when compared across species. Here, we tested the association between lifespan and telomere length in African annual killifish. We analyzed telomere length in 18 Nothobranchius strains derived from diverse habitats and measured the laboratory lifespan of...

Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viabili...

Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may sh...

Significance Cancer incidence increases exponentially in human midlife. Even though mutation accumulation in somatic tissues results in increased tumorigenesis, it is currently not understood how aging contributes to cancer. Telomeres, the ends of eukaryotic linear chromosomes, shorten with each cell division. Here, we show that telomere shortening...

Despite promising preclinical results, average response rates to anti-VEGF therapies, such as bevacizumab, are reduced for most cancers, while incurring in remarkable costs and side effects. Currently, there are no biomarkers available to select patients that can benefit from this therapy. Depending on the individual tumor, anti-VEGF therapies can...

The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The admin-istration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-medi...

Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, pro...

Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, pro...

Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, pro...

Malfunctions of circadian clock trigger abnormal cellular processes and influence tumorigenesis. Using an in vitro and in vivo xenograft model, we show that circadian clock disruption via the downregulation of the core-clock genes BMAL1, PER2, and NR1D1 impacts the circadian phenotype of MYC, WEE1, and TP53, and affects proliferation, apoptosis, an...

Background: VEGF-A is the most potent pro-angiogenic factor and is upregulated in a variety of tumors. Therapies were developed to neutralize VEGF signalling, such as Bevacizumab (Bev). Despite promising pre-clinical results, the average response rate to Bev is reduced for most cancers, with significant side effects. In breast cancer (BC) several s...

Background & aims: Vascular invasion is a major prognostic factor in hepatocellular carcinoma (HCC). We previously identified histone H4 acetylated on lysine 16 (H4K16ac), a histone modification involved in transcription activation, as a biomarker of microvascular invasion (mVI) in HCC. This study aimed to investigate the role of hMOF, the histone...

Progressive telomere shortening during lifespan is associated with increased genome instability, block to cell proliferation and aging. Apoptosis and senescence are the two main cellular outcomes upon irreversible cell damage. In this study, we show a transition between apoptosis to senescence in cells of two independent tissues in telomerase zebra...

Background Whereas the role of neoadjuvant radiotherapy in rectal cancer is well-established, the ability to discriminate between radioresistant and radiosensitive tumors before starting treatment is still a crucial unmet need. Here we aimed to develop an in vivo test to directly challenge living cancer cells to radiotherapy, using zebrafish xenogr...

Cancer incidence increases exponentially with age, when human telomeres are shorter. Similarly, telomerase mutant zebrafish ( tert ) have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppre...

The centrosome is composed of two centrioles surrounded by a microtubule-nucleating pericentriolar material (PCM). Although centrioles are known to regulate PCM assembly, it is less known whether and how the PCM contributes to centriole assembly. Here we investigate the interaction between centriole components and the PCM by taking advantage of fis...

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Telomeres, the protective ends of eukaryotic chromosomes, are replicated through concerted actions of conventional DNA poly-merases and elongated by telomerase, but the regulation of this process is not fully understood. Telomere replication requires (Ctc1/ Cdc13)-Stn1-Ten1, a telomeric ssDNA-binding complex homologous to RPA. Here, we show that th...

Cancer is a disease of the elderly, and old age is its largest risk factor. With age, DNA damage accumulates continuously, increasing the chance of malignant transformation. The zebrafish has emerged as an important vertebrate model to study these processes. Key mechanisms such as DNA damage responses and cellular senescence can be studied in zebra...

List of human and zebrafish genes involved in DDR, and the corresponding tools (mutant, antibody, etc.) available for zebrafish research. In the second page of the excel file, gene ontology classification of the same gene.

Whereas the role of neoadjuvant radiotherapy in rectal cancer is well-established, the ability to discriminate between radioresistant and radiosensitive tumors before starting treatment is still a crucial unmet need. Here we aimed to develop an in vivo test to directly challenge living cancer cells to radiotherapy, using zebrafish xenografts. Metho...

p>Creating ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous triggers offers the possibility for precise and traceless drug activation. However, ensuring localization of the trigger as well as the prodrug at the diseased tissue is complex while essential for...

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Here we show, through direct live-cell imaging of young, middle-aged, and old-aged primary human dermal fibroblasts, that aneuploidy increases with aging due to general dysfunction of the mitotic m...

Introduction Despite great advances in biomarker-driven therapies, we still lack methods to predict how a specific cancer in a unique patient will respond to a given therapy. This exposes some patients to unnecessary toxicities and delays access to other potentially effective therapies. Material and methods Recently, we developed and optimised zeb...

The centrosome is composed of two centrioles surrounded by a microtubule-nucleating pericentriolar matrix (PCM). Centrioles regulate matrix assembly. Here we ask whether the matrix also regulates centriole assembly. To define the interaction between the matrix and individual centriole components, we take advantage of a heterologous expression syste...

Mammalian CST (CTC1-STN1-TEN1) complex fulfills numerous functions including rescue of the stalled replication forks and termination of telomerase action. In fission yeast lacking the CTC1 ortholog, the Stn1-Ten1 complex restricts telomerase action via its sumoylation-mediated interaction with Tpz1TPP1. We identify a small ubiquitin-like modifier (...

Katsu and Baker (1) highlight a potential weakness in using zebrafish patient-derived xenografts (zPDX) (2) for endocrine-dependent tumors. Katsu and Baker (1) report that, unlike human estrogen receptor (ER), progesterone may activate zebrafish mineralocorticoid receptor (MR) instead of inhibiting it (3). Treatment of zPDXs with progesterone would...

Aneuploidy, an abnormal chromosome number, has been linked to aging and age-associated diseases, but the underlying molecular mechanisms remain unknown. Supported by direct live-cell imaging of young, middle-aged and old-aged primary human dermal fibroblasts, we found that aneuploidy increases with aging due to general dysfunction of the mitotic ma...

Significance Despite advances in targeted cancer treatments, we still lack methods to predict how a specific cancer will respond to a given therapy. As a consequence, patients go through rounds of trial-and-error approaches based on guidelines to find the best treatment, often subjected to unnecessary toxicity. Using cell lines, we used zebrafish l...

[This corrects the article DOI: 10.1371/journal.pgen.1003214.].

Correction and copies of the original gel scans from where lanes were selected. (DOCX)

One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so f...

Age is the highest risk factor for some of the most prevalent human diseases, including cancer. Telomere shortening is thought to play a central role in the aging process in humans. The link between telomeres and aging is highlighted by the fact that genetic diseases causing telomerase deficiency are associated with premature aging and increased ri...

Eukaryotic cells use two principal mechanisms for repairing DNA double-strand breaks (DSBs): homologous recombination (HR) and nonhomologous end-joining (NHEJ). DSB repair pathway choice is strongly regulated during the cell cycle. Cyclin-dependent kinase 1 (Cdk1) activates HR by phosphorylation of key recombination factors. However, a mechanism fo...

Chromosomal rearrangements are mutations contributing to both within and between species variation; however their contribution to fitness is yet to be measured. Here we show that chromosomal rearrangements are pervasive in natural isolates of Schizosaccharomyces pombe and contribute to reproductive isolation. To determine the fitness effects of chr...

The final step of cytoplasmic mRNA degradation proceeds in either a 50-30 direction catalysed by Xrn1 or in a 30-50 direction catalysed by the exosome. Dis3/Rrp44, an RNase II family protein, is the catalytic subunit of the exosome. In humans, there are three paralogues of this enzyme: DIS3, DIS3L, and DIS3L2. In this work, we identified a novel Sc...

Telomeres protect eukaryotic chromosomes from illegitimate end-to-end fusions. When this function fails, dicentric chromosomes are formed, triggering breakage-fusion-bridge cycles and genome instability. How efficient is this protection mechanism in normal cells is not fully understood. We created a positive selection assay aimed at capturing chrom...