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Papers by Joan Bech-serra

Hematological Oncology, 2021

PLoS Genetics, 2014

Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of prematur... more Exposure to ultraviolet (UV) radiation from sunlight accounts for 90% of the symptoms of premature skin aging and skin cancer. The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults. Here we analyzed the role of LKB1 in a UV-dependent mouse skin cancer model and show that LKB1 haploinsufficiency is enough to impede UVB-induced DNA damage repair, contributing to tumor development driven by aberrant growth factor signaling. We demonstrate that LKB1 and its downstream kinase NUAK1 bind to CDKN1A. In response to UVB irradiation, LKB1 together with NUAK1 phosphorylates CDKN1A regulating the DNA damage response. Upon UVB treatment, LKB1 or NUAK1 deficiency results in CDKN1A accumulation, impaired DNA repair and resistance to apoptosis. Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer. Altogether, our results identify LKB1 as a DNA damage sensor protein regulating skin UV-induced DNA damage response.

Brain pathology (Zurich, Switzerland), Jan 3, 2018

Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing a... more Aging-related tau astrogliopathy (ARTAG) is defined by the presence of two types of tau-bearing astrocytes: thorn-shaped astrocytes (TSAs) and granular/fuzzy astrocytes in the brain of old-aged individuals. The present study is focused on TSAs in rare forms of ARTAG with no neuronal tau pathology or restricted to entorhinal and transentorhinal cortices, to avoid bias from associated tauopathies. TSAs show 4Rtau phosphorylation at several specific sites and abnormal tau conformation, but they lack ubiquitin and they are not immunostained with tau-C3 antibodies which recognize truncated tau at Asp421. Astrocytes in ARTAG have atrophic processes, reduced glial fibrillary acidic protein (GFAP) and increased superoxide dismutase 2 (SOD2) immunoreactivity. Gel electrophoresis and western blotting of sarkosyl-insoluble fractions reveal a pattern of phospho-tau in ARTAG characterized by two bands of 68 and 64 kDa, and several middle bands between 35 and 50 kDa which differ from what is seen...

Journal of Cachexia, Sarcopenia and Muscle, 2022

The lack of dystrophin expression in Duchenne muscular dystrophy (DMD) induces muscle fibre and r... more The lack of dystrophin expression in Duchenne muscular dystrophy (DMD) induces muscle fibre and replacement by fibro‐adipose tissue. Although the role of some growth factors in the process of fibrogenesis has been studied, pathways activated by PDGF‐AA have not been described so far. Our aim was to study the molecular role of PDGF‐AA in the fibrotic process of DMD.

ABSTRACTThe lack of dystrophin expression in Duchenne muscular dystrophy (DMD) leads to muscle ne... more ABSTRACTThe lack of dystrophin expression in Duchenne muscular dystrophy (DMD) leads to muscle necrosis and replacement of muscle tissue by fibro-adipose tissue. Although the role of some growth factors in the process of fibrogenesis has been previously studied, the pathways that are activated by PDGF-AA in muscular dystrophies have not been described so far. Herein we report the effects of PDGF-AA on the fibrotic process in muscular dystrophies by performing a quantitative proteomic study in DMD isolated fibro-adipogenic precursor cells (FAPs) treated with PDGF-AA. In vitro studies showed that RhoA/ROCK2 pathway is activated by PDGF-AA and induces the activation of FAPs. The inhibition of RhoA/ROCK signalling pathway by C3-exoenzyme or fasudil attenuated the effects of PDGF-AA. The blocking effects of RhoA/ROCK pathway were analysed in the dba/2J-mdx murine model with fasudil. Grip strength test showed an improvement in the muscle function and histological studies demonstrated redu...

Nature Communications

The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients wit... more The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down r...

Clinical Cancer Research

PURPOSE Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non-Hodgkin l... more PURPOSE Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non-Hodgkin lymphoma (B-NHL), no clinically-relevant biomarker has been associated to these agents so far. The relevance of phosphoproteomic profiling for the early identification of BTKi responders remains underexplored. EXPERIMENTAL DESIGN A set of six clinical samples from an ongoing phase 1 trial dosing chronic lymphocytic leukemia (CLL) patients with TG-1701, a novel irreversible and highly specific BTKi, were characterized by phosphoproteomic and RNA-seq analysis. The activity of TG-1701 was evaluated in a panel of eleven B-NHL cell lines and mouse xenografts, including two NFκB- and BTKC481S-driven BTKi resistant models. Biomarker validation and signal transduction analysis were conducted through real-time PCR, western blot, immunostaining and gene knock-out (KO) experiments. RESULTS A non-supervised, phosphoproteomic-based clustering did match the early clinical outcomes of CLL patients and separated a group of "early-responders" from a group of "late-responders". This clustering was based on a selected list of 96 phosphosites with Ikaros-pSer442/445 as a potential biomarker for TG-1701 efficacy. TG-1701 treatment was further shown to blunt Ikaros gene signature, including YES1 and MYC, in early-responder patients as well as in BTKi-sensitive B-NHL cell lines and xenografts. In contrast, Ikaros nuclear activity and signaling remained unaffected by the drug in vitro and in vivo, in late-responder patients and in BTKC481S, BTKKO and non-canonical NFκB models. CONCLUSIONS These data validate phosphoproteomic as a valuable tool for the early detection of response to BTK inhibition in the clinic, and for the determination of drug mechanism of action.

Journal of Proteome Research

GigaScience, May 1, 2018

Protein phosphatase 2A (PP2A) is a family of conserved serine/threonine phosphatases involved in ... more Protein phosphatase 2A (PP2A) is a family of conserved serine/threonine phosphatases involved in several essential aspects of cell growth and proliferation. PP2ACdc55 phosphatase has been extensively related to cell cycle events in budding yeast; however, few PP2ACdc55 substrates have been identified. Here, we performed a quantitative mass spectrometry approach to reveal new substrates of PP2ACdc55 phosphatase and new PP2A-related processes in mitotic arrested cells. We identified 62 statistically significant PP2ACdc55 substrates involved mainly in actin-cytoskeleton organization. In addition, we validated new PP2ACdc55 substrates such as Slk19 and Lte1, involved in early and late anaphase pathways, and Zeo1, a component of the cell wall integrity pathway. Finally, we constructed docking models of Cdc55 and its substrate Mob1. We found that the predominant interface on Cdc55 is mediated by a protruding loop consisting of residues 84-90, thus highlighting the relevance of these amino...

Scientific reports, Jan 5, 2017

Conditionally disordered proteins are either ordered or disordered depending on the environmental... more Conditionally disordered proteins are either ordered or disordered depending on the environmental context. The substrates of the mitochondrial intermembrane space (IMS) oxidoreductase Mia40 are synthesized on cytosolic ribosomes and diffuse as intrinsically disordered proteins to the IMS, where they fold into their functional conformations; behaving thus as conditionally disordered proteins. It is not clear how the sequences of these polypeptides encode at the same time for their ability to adopt a folded structure and to remain unfolded. Here we characterize the disorder-to-order transition of a Mia40 substrate, the human small copper chaperone Cox17. Using an integrated real-time approach, including chromatography, fluorescence, CD, FTIR, SAXS, NMR, and MS analysis, we demonstrate that in this mitochondrial protein, the conformational switch between disordered and folded states is controlled by the formation of a single disulfide bond, both in the presence and in the absence of Mi...

Journal of Proteomics, 2016

Background / Purpose: Metalloproteases play a complex role in tumor progression. Using proteomic ... more Background / Purpose: Metalloproteases play a complex role in tumor progression. Using proteomic approaches to identify the array of specific substrates of a metalloprotease can help to unveil its role in tumor growth and metastasis.Proteomic screening of proteins released to the extracellular medium by model tumor cell systems can identify substrates of metalloproteases relevant for tumor progression. Main conclusion: A SILAC experiment on MCF7 breast cancer cells identified vasorin as a substrate of the protease ADAM17. Vasorin was shown to have a role in the regulation of TGFB signaling and the epithelial to mesenchymal transition.

Journal of Proteome Research, 2015