Colorectal cancer ‐initiating cells caught in the act
Our increased awareness of the clonal organization of many hematological and solid cancers has dramatically changed our view on the design of novel therapeutic approaches for cancer. Tumor‐initiating cells (TIC) (a.k.a. cancer stem cells) are on the apex in this hierarchy and can self‐renew and differentiate, thereby continuously fueling tumor growth and metastasis formation. This process was previously thought to be unidirectional. Self‐renewing TIC therefore represent highly attractive targets for therapeutic intervention.
A poignant commentary on three recent papers using genetic fate mapping to demonstrate that ...
Source: EMBO Molecular Medicine - May 30, 2017 Category: Molecular Biology Authors: Sebastian M Dieter, Hanno Glimm, Claudia R Ball Tags: News & Views Source Type: research
MSTO1 is a cytoplasmic pro ‐mitochondrial fusion protein, whose mutation induces myopathy and ataxia in humans
Abstract
The protein MSTO1 has been localized to mitochondria and linked to mitochondrial morphology, but its specific role has remained unclear. We identified a c.22G > A (p.Val8Met) mutation of MSTO1 in patients with minor physical abnormalities, myopathy, ataxia, and neurodevelopmental impairments. Lactate stress test and myopathological results suggest mitochondrial dysfunction. In patient fibroblasts, MSTO1 mRNA and protein abundance are decreased, mitochondria display fragmentation, aggregation, and decreased network continuity and fusion activity. These characteristics can be reversed by genetic rescue. Short...
Source: EMBO Molecular Medicine - May 29, 2017 Category: Molecular Biology Authors: Aniko Gal, Peter Balicza, David Weaver, Shamim Naghdi, Suresh K Joseph, P éter Várnai, Tibor Gyuris, Attila Horváth, Laszlo Nagy, Erin L Seifert, Maria Judit Molnar, György Hajnóczky Tags: Research Article Source Type: research
A novel epigenetic AML1 ‐ETO/THAP10/miR‐383 mini‐circuitry contributes to t(8;21) leukaemogenesis
This study demonstrated that a novel hypermethylated zinc finger‐containing protein, THAP10, is a target gene and can be epigenetically suppressed by AML1‐ETO at the transcriptional level in t(8;21) AML. Our findings also show that THAP10 is a bona fide target of miR‐383 that can be epigenetically activated by the AML1‐ETO recruiting co‐activator p300. In this study, we demonstrated that epigenetic suppression of THAP10 is the mechanistic link between AML1‐ETO fusion proteins and tyrosine kinase cascades. In addition, we showed that THAP10 is a nuclear protein that inhibits myeloid proliferation and promotes di...
Source: EMBO Molecular Medicine - May 24, 2017 Category: Molecular Biology Authors: Yonghui Li, Qiaoyang Ning, Jinlong Shi, Yang Chen, Mengmeng Jiang, Li Gao, Wenrong Huang, Yu Jing, Sai Huang, Anqi Liu, Zhirui Hu, Daihong Liu, Lili Wang, Clara Nervi, Yun Dai, Michael Q Zhang, Li Yu Tags: Research Article Source Type: research
Specific biomarkers for C9orf72 FTD/ALS could expedite the journey towards effective therapies
A hexanucleotide repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The repeats are translated into five different dipeptide repeat proteins (DPRs). In this issue, Lehmer et al (2017) demonstrate that one of these DPRs, poly(GP), can be measured in the CSF of individuals with C9orf72 mutations. In conjunction with the findings from another recent study (Gendron et al, 2017), these DPR biomarkers may prove to be extremely valuable in the quest for effective therapies for C9FTD/ALS.
Isaacs and colleagues discuss two recent studies showing how a dipeptide repeat protein, poly(GP), can be measure...
Source: EMBO Molecular Medicine - May 22, 2017 Category: Molecular Biology Authors: Rubika Balendra, Thomas G Moens, Adrian M Isaacs Tags: News & Views Source Type: research
CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib
Abstract
Cyclin D‐CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER‐positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate‐limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post‐translational mo...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Eric Rasp é, Katia Coulonval, Jaime M Pita, Sabine Paternot, Françoise Rothé, Laure Twyffels, Sylvain Brohée, Ligia Craciun, Denis Larsimont, Véronique Kruys, Flavienne Sandras, Isabelle Salmon, Steven Van Laere, Martine Piccart, Michail Ignatiadis, Tags: Research Article Source Type: research
CXCL12 α/SDF‐1 from perisynaptic Schwann cells promotes regeneration of injured motor axon terminals
We report here that CXCL12α, also abbreviated as stromal‐derived factor‐1 (SDF‐1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by α‐latrotoxin. CXCL12α acts via binding to the neuronal CXCR4 receptor. A CXCL12α‐neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration in vivo. Recombinant CXCL12α in vivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons in vitro. These findings indicate that the CXCL12α‐CXCR4 axis pla...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Samuele Negro, Francesca Lessi, Elisa Duregotti, Paolo Aretini, Marco La Ferla, Sara Franceschi, Michele Menicagli, Elisanna Bergamin, Egle Radice, Marcus Thelen, Aram Megighian, Marco Pirazzini, Chiara M Mazzanti, Michela Rigoni, Cesare Montecucco Tags: Report Source Type: research
SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia in homozygotes
This study confirms SPINK2 in that role and finds it essential for spermiogenesis as SPINK2 deficiency induces a post meiotic block at the round spermatid stage leading to azoospermia in mice and men. (Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Zine ‐Eddine Kherraf, Marie Christou‐Kent, Thomas Karaouzene, Amir Amiri‐Yekta, Guillaume Martinez, Alexandra S Vargas, Emeline Lambert, Christelle Borel, Béatrice Dorphin, Isabelle Aknin‐Seifer, Michael J Mitchell, Catherine Metzler‐Guillemain Tags: Research Article Source Type: research
γ‐Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct
Abstract
γ‐Secretase inhibitors (GSIs) are being actively repurposed as cancer therapeutics based on the premise that inhibition of NOTCH1 signaling in select cancers is therapeutic. Using novel assays to probe effects of GSIs against a broader panel of substrates, we demonstrate that clinical GSIs are pharmacologically distinct. GSIs show differential profiles of inhibition of the various NOTCH substrates, with some enhancing cleavage of other NOTCH substrates at concentrations where NOTCH1 cleavage is inhibited. Several GSIs are also potent inhibitors of select signal peptide peptidase (SPP/SPPL) family members. Exten...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Yong Ran, Fokhrul Hossain, Antonio Pannuti, Christian B Lessard, Gabriela Z Ladd, Joo In Jung, Lisa M Minter, Barbara A Osborne, Lucio Miele, Todd E Golde Tags: Research Article Source Type: research
Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease
Abstract
Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss‐of‐function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase‐inactive laforin rescues the laforin‐deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify br...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Felix Nitschke, Mitchell A Sullivan, Peixiang Wang, Xiaochu Zhao, Erin E Chown, Ami M Perri, Lori Israelian, Lucia Juana ‐López, Paola Bovolenta, Santiago Rodríguez de Córdoba, Martin Steup, Berge A Minassian Tags: Research Article Source Type: research
Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases
(Source: EMBO Molecular Medicine)
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: J örg T Regula, Peter Lundh von Leithner, Richard Foxton, Veluchamy A Barathi, Chui Ming Gemmy Cheung, Sai Bo Bo Tun, Yeo Sia Wey, Daiju Iwata, Miroslav Dostalek, Jörg Moelleken, Kay G Stubenrauch, Everson Nogoceke, Gabriella Widmer, Pamela Strassburger Tags: Expression of Concern Source Type: research
Succession of transiently active tumor ‐initiating cell clones in human pancreatic cancer xenografts
Abstract
Although tumor‐initiating cell (TIC) self‐renewal has been postulated to be essential in progression and metastasis formation of human pancreatic adenocarcinoma (PDAC), clonal dynamics of TICs within PDAC tumors are yet unknown. Here, we show that long‐term progression of PDAC in serial xenotransplantation is driven by a succession of transiently active TICs producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TICs revealed that individual tumors are generated by distinct sets of TICs with very little overlap between subsequent xenograft generations. An une...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Claudia R Ball, Felix Oppel, Karl Roland Ehrenberg, Taronish D Dubash, Sebastian M Dieter, Christopher M Hoffmann, Ulrich Abel, Friederike Herbst, Moritz Koch, Jens Werner, Frank Bergmann, Naveed Ishaque, Manfred Schmidt, Christof Kalle, Claudia Scholl, S Tags: Research Article Source Type: research
Loss of Mpdz impairs ependymal cell integrity leading to perinatal ‐onset hydrocephalus in mice
Abstract
Hydrocephalus is a common congenital anomaly. LCAM1 and MPDZ (MUPP1) are the only known human gene loci associated with non‐syndromic hydrocephalus. To investigate functions of the tight junction‐associated protein Mpdz, we generated mouse models. Global Mpdz gene deletion or conditional inactivation in Nestin‐positive cells led to formation of supratentorial hydrocephalus in the early postnatal period. Blood vessels, epithelial cells of the choroid plexus, and cilia on ependymal cells, which line the ventricular system, remained morphologically intact in Mpdz‐deficient brains. However, flow of cerebrospin...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Anja Feldner, M Gordian Adam, Fabian Tetzlaff, Iris Moll, Dorde Komljenovic, Felix Sahm, Tobias B äuerle, Hiroshi Ishikawa, Horst Schroten, Thomas Korff, Ilse Hofmann, Hartwig Wolburg, Andreas Deimling, Andreas Fischer Tags: Research Article Source Type: research
DOK7 gene therapy enhances motor activity and life span in ALS model mice
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target. We previously demonstrated th...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Sadanori Miyoshi, Tohru Tezuka, Sumimasa Arimura, Taro Tomono, Takashi Okada, Yuji Yamanashi Tags: Report Source Type: research
A genome editing approach to study cancer stem cells in human tumors
Abstract
The analysis of stem cell hierarchies in human cancers has been hampered by the impossibility of identifying or tracking tumor cell populations in an intact environment. To overcome this limitation, we devised a strategy based on editing the genomes of patient‐derived tumor organoids using CRISPR/Cas9 technology to integrate reporter cassettes at desired marker genes. As proof of concept, we engineered human colorectal cancer (CRC) organoids that carry EGFP and lineage‐tracing cassettes knocked in the LGR5 locus. Analysis of LGR5‐EGFP+ cells isolated from organoid‐derived xenografts demonstrated that these...
Source: EMBO Molecular Medicine - May 1, 2017 Category: Molecular Biology Authors: Carme Cortina, Gemma Turon, Diana Stork, Xavier Hernando ‐Momblona, Marta Sevillano, Mònica Aguilera, Sébastien Tosi, Anna Merlos‐Suárez, Camille Stephan‐Otto Attolini, Elena Sancho, Eduard Batlle Tags: Report Source Type: research
Transient transcription factor (OSKM) expression is key towards clinical translation of in vivo cell reprogramming
Reprogramming adult, fully differentiated cells to pluripotency in vivo via Oct3/4, Sox2, Klf4 and c‐Myc (OSKM) overexpression has proved feasible in various independent studies and could be used to induce tissue regeneration owing to the proliferative capacity and differentiation potential of the reprogrammed cells. However, a number of these reports have described the generation of teratomas caused by sustained reprogramming, which precludes the therapeutic translation of this technology. A recent study by the Izpisúa‐Belmonte laboratory described a cyclic regime for short‐term OSKM expression in vivo that preve...
Source: EMBO Molecular Medicine - April 28, 2017 Category: Molecular Biology Authors: Irene L ázaro, Giulio Cossu, Kostas Kostarelos Tags: Commentary Source Type: research
