TGF ‐β1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via up‐regulation of IL‐17RB
Abstract
Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor‐draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis. Up‐regulation of oncogenic Il‐17rb in cancer cells derived from TDLNs contributes...
Source: EMBO Molecular Medicine - October 1, 2017 Category: Molecular Biology Authors: Shih ‐Chia Huang, Pei‐Chi Wei, Wendy W Hwang‐Verslues, Wen‐Hung Kuo, Yung‐Ming Jeng, Chun‐Mei Hu, Jin‐Yuh Shew, Chiun‐Sheng Huang, King‐Jen Chang, Eva Y‐HP Lee, Wen‐Hwa Lee Tags: Research Article Source Type: research
Treatment of hypertension by increasing impaired endothelial TRPV4 ‐KCa2.3 interaction
We report that transient receptor potential vanilloid 4 (TRPV4) interacts with Ca2+‐activated potassium channel 3 (KCa2.3) in endothelial cells (ECs) from small resistance arteries of normotensive humans, while ECs from hypertensive patients show a reduced interaction between TRPV4 and KCa2.3. Murine hypertension models, induced by high‐salt diet, N(G)‐nitro‐l‐arginine intake, or angiotensin II delivery, showed decreased TRPV4‐KCa2.3 interaction in ECs. Perturbation of the TRPV4‐KCa2.3 interaction in mouse ECs by overexpressing full‐length KCa2.3 or defective KCa2.3 had hypotensive or hypertensive effects, ...
Source: EMBO Molecular Medicine - September 12, 2017 Category: Molecular Biology Authors: Dongxu He, Qiongxi Pan, Zhen Chen, Chunyuan Sun, Peng Zhang, Aiqin Mao, Yaodan Zhu, Hongjuan Li, Chunxiao Lu, Mingxu Xie, Yin Zhou, Daoming Shen, Chunlei Tang, Zhenyu Yang, Jian Jin, Xiaoqiang Yao, Bernd Nilius, Xin Ma Tags: Report Source Type: research
Pathogen ‐specific B‐cell receptors drive chronic lymphocytic leukemia by light‐chain‐dependent cross‐reaction with autoantigens
Abstract
Several lines of evidence indirectly suggest that antigenic stimulation through the B‐cell receptor (BCR) supports chronic lymphocytic leukemia (CLL) development. In addition to self‐antigens, a number of microbial antigens have been proposed to contribute to the selection of the immunoglobulins expressed in CLL. How pathogen‐specific BCRs drive CLL development remains, however, largely unexplored. Here, we utilized mouse models of CLL pathogenesis to equip B cells with virus‐specific BCRs and study the effect of antigen recognition on leukemia growth. Our results show that BCR engagement is absolutely req...
Source: EMBO Molecular Medicine - September 12, 2017 Category: Molecular Biology Authors: Nereida Jim énez de Oya, Marco De Giovanni, Jessica Fioravanti, Rudolf Übelhart, Pietro Di Lucia, Amleto Fiocchi, Stefano Iacovelli, Dimitar G Efremov, Federico Caligaris‐Cappio, Hassan Jumaa, Paolo Ghia, Luca G Guidotti, Matteo Iannacone Tags: Report Source Type: research
Sequence variation in PPP1R13L results in a novel form of cardio ‐cutaneous syndrome
(Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - September 4, 2017 Category: Molecular Biology Authors: Tzipora C Falik ‐Zaccai, Yiftah Barsheshet, Hanna Mandel, Meital Segev, Avraham Lorber, Shachaf Gelberg, Limor Kalfon, Shani Ben Haroush, Adel Shalata, Liat Gelernter‐Yaniv, Sarah Chaim, Dorith Raviv Shay, Morad Khayat, Michal Werbner, Inbar Levi, Yis Tags: Corrigendum Source Type: research
Peroxisome proliferator ‐activated receptor gamma (PPARγ) regulates lactase expression and activity in the gut
This study aims at characterizing PPARγ target genes involved in intestinal metabolic functions. In microarray analysis, the LCT gene was the most upregulated by PPARγ agonists in Caco‐2 cells. We confirmed that PPARγ agonists were able to increase the expression and activity of LCT both in vitro and in vivo in the proximal small bowel of rodents. The functional response element activated by PPARγ was identified in the promoter of the human LCT gene. PPARγ modulation was able to improve symptoms induced by lactose‐enriched diet in weaned rats. Our results demonstrate that PPARγ regulates LCT expression, and sug...
Source: EMBO Molecular Medicine - September 1, 2017 Category: Molecular Biology Authors: Mathurin Fumery, Silvia Speca, Audrey Langlois, Anne ‐Marie Davila, Caroline Dubuquoy, Marta Grauso, Anthony Martin Mena, Martin Figeac, Daniel Metzger, Christel Rousseaux, Jean‐Frederic Colombel, Laurent Dubuquoy, Pierre Desreumaux, Benjamin Bertin Tags: Report Source Type: research
Profiling MHC II immunopeptidome of blood ‐stage malaria reveals that cDC1 control the functionality of parasite‐specific CD4 T cells
Abstract
In malaria, CD4 Th1 and T follicular helper (TFH) cells are important for controlling parasite growth, but Th1 cells also contribute to immunopathology. Moreover, various regulatory CD4 T‐cell subsets are critical to hamper pathology. Yet the antigen‐presenting cells controlling Th functionality, as well as the antigens recognized by CD4 T cells, are largely unknown. Here, we characterize the MHC II immunopeptidome presented by DC during blood‐stage malaria in mice. We establish the immunodominance hierarchy of 14 MHC II ligands derived from conserved parasite proteins. Immunodominance is shaped differently ...
Source: EMBO Molecular Medicine - September 1, 2017 Category: Molecular Biology Authors: Marion Draheim, Myriam F Wlodarczyk, Karine Crozat, Jean ‐Michel Saliou, Tchilabalo Dilezitoko Alayi, Stanislas Tomavo, Ali Hassan, Anna Salvioni, Claudia Demarta‐Gatsi, John Sidney, Alessandro Sette, Marc Dalod, Antoine Berry, Olivier Silvie, Nicolas Tags: Research Article Source Type: research
Mutant CTNNB1 and histological heterogeneity define metabolic subtypes of hepatoblastoma
Abstract
Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β‐catenin‐driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter GLUT3 is a direc...
Source: EMBO Molecular Medicine - September 1, 2017 Category: Molecular Biology Authors: Stefania Crippa, Pierre ‐Benoit Ancey, Jessica Vazquez, Paolo Angelino, Anne‐Laure Rougemont, Catherine Guettier, Vincent Zoete, Mauro Delorenzi, Olivier Michielin, Etienne Meylan Tags: Research Article Source Type: research
Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease
Abstract
Neonatal chronic lung disease (nCLD) affects a significant number of neonates receiving mechanical ventilation with oxygen‐rich gas (MV‐O2). Regardless, the primary molecular driver of the disease remains elusive. We discover significant enrichment for SNPs in the PDGF‐Rα gene in preterms with nCLD and directly test the effect of PDGF‐Rα haploinsufficiency on the development of nCLD using a preclinical mouse model of MV‐O2. In the context of MV‐O2, attenuated PDGF signaling independently contributes to defective septation and endothelial cell apoptosis stemming from a PDGF‐Rα‐dependent reduction...
Source: EMBO Molecular Medicine - September 1, 2017 Category: Molecular Biology Authors: Prajakta Oak, Tina Pritzke, Isabella Thiel, Markus Koschlig, Daphne S Mous, Anita Windhorst, Noopur Jain, Oliver Eickelberg, Kai Foerster, Andreas Schulze, Wolfgang Goepel, Tobias Reicherzer, Harald Ehrhardt, Robbert J Rottier, Peter Ahnert, Ludwig Gortne Tags: Research Article Source Type: research
Therapeutic gene editing in CD34+ hematopoietic progenitors from Fanconi anemia patients
Abstract
Gene targeting constitutes a new step in the development of gene therapy for inherited diseases. Although previous studies have shown the feasibility of editing fibroblasts from Fanconi anemia (FA) patients, here we aimed at conducting therapeutic gene editing in clinically relevant cells, such as hematopoietic stem cells (HSCs). In our first experiments, we showed that zinc finger nuclease (ZFN)‐mediated insertion of a non‐therapeutic EGFP‐reporter donor in the AAVS1 “safe harbor” locus of FA‐A lymphoblastic cell lines (LCLs), indicating that FANCA is not essential for the editing of human cells. When...
Source: EMBO Molecular Medicine - September 1, 2017 Category: Molecular Biology Authors: Bego ña Diez, Pietro Genovese, Francisco J Roman‐Rodriguez, Lara Alvarez, Giulia Schiroli, Laura Ugalde, Sandra Rodriguez‐Perales, Julian Sevilla, Cristina Diaz de Heredia, Michael C Holmes, Angelo Lombardo, Luigi Naldini, Juan Antonio Bueren, Paula Tags: Research Article Source Type: research
An Alzheimer ‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
Abstract
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)‐like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2‐dependent phagocytosis. Using mass spectrometry, we have now determined the cleavage site of ...
Source: EMBO Molecular Medicine - August 30, 2017 Category: Molecular Biology Authors: Kai Schlepckow, Gernot Kleinberger, Akio Fukumori, Regina Feederle, Stefan F Lichtenthaler, Harald Steiner, Christian Haass Tags: Report Source Type: research
TREM2 shedding by cleavage at the H157 ‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant
Abstract
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2‐expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N‐terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic proteas...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Peter Thornton, Jean Sevalle, Mike J Deery, Graham Fraser, Ye Zhou, Sara St åhl, Elske H Franssen, Roger B Dodd, Seema Qamar, Beatriz Gomez Perez‐Nievas, Louise SC Nicol, Susanna Eketjäll, Jefferson Revell, Clare Jones, Andrew Billinton, Peter H St Ge Tags: Research Article Source Type: research
Genome editing for scalable production of alloantigen ‐free lentiviral vectors for in vivo gene therapy
Abstract
Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large‐scale manufacturing and raises concerns for in vivo applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell‐derived polymorphic class‐I major histocompatibility complexes (MHC‐I) are incorporated into the LV surface and trigger allogeneic T‐cell responses. By disrupting the beta‐2 microglobulin gene in producer cells, we obtained MHC‐free LV with substantially reduced immunogenicity. We introduce...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Michela Milani, Andrea Annoni, Sara Bartolaccini, Mauro Biffi, Fabio Russo, Tiziano Di Tomaso, Andrea Raimondi, Johannes Lengler, Michael C Holmes, Friedrich Scheiflinger, Angelo Lombardo, Alessio Cantore, Luigi Naldini Tags: Research Article Source Type: research
Thwarting endogenous stress: BRCA protects against aldehyde toxicity
Homologous recombination (HR) and the Fanconi Anemia (FA) pathways constitute essential repair pathways for DNA damage, which includes DNA double‐stranded breaks (DSB) and inter‐strand cross‐links (ICL), respectively. Germline mutations affecting a single copy of the HR factors BRCA1 and BRCA2 predispose individuals to cancers of the breast, ovary, prostate, and pancreas. Cells deficient for BRCA proteins display high levels of genome instability due to defective repair of endogenous DSBs and are also exquisitely sensitive to DNA‐damaging agents. In addition to their roles in repair of DSBs and ICLs, HR and FA prot...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Arnab Ray Chaudhuri, Andr é Nussenzweig Tags: News & Views Source Type: research
Src ‐dependent phosphorylation of μ‐opioid receptor at Tyr336 modulates opiate withdrawal
Abstract
Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ‐opioid receptor (MOR) at Tyr336 by Src after prolonged opiate treatment in vitro. Here, we report that the Src‐mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Lei Zhang, Cherkaouia Kibaly, Yu ‐Jun Wang, Chi Xu, Kyu Young Song, Patrick W McGarrah, Horace H Loh, Jing‐Gen Liu, Ping‐Yee Law Tags: Research Article Source Type: research
One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology
Abstract
The discovery of a mutation in a specific gene can be very important for determining the pathophysiology underlying the disease of a patient and may also help to decide the best treatment protocol on an individual basis. However, sometimes the discovery of mutations in new proteins advances our comprehension in a more widespread manner. The growth hormone (GH)/insulin‐like growth factor (IGF)‐1 axis is fundamental for systemic growth, but is also involved in many other important processes. Our understanding of this system in physiology and pathophysiology has advanced throughout the years with each discovery o...
Source: EMBO Molecular Medicine - August 1, 2017 Category: Molecular Biology Authors: Jes ús Argente, Julie A Chowen, Luis A Pérez‐Jurado, Jan Frystyk, Claus Oxvig Tags: Review Source Type: research
