Volume 3 (2019)
Stress granules regulate paraspeckles: RNP granule continuum at work
Haiyan An1 and Tatyana A. Shelkovnikova1
Eukaryotic cells contain a variety of large, multicomponent RNA-protein complexes termed ribonucleoprotein (RNP) granules. RNP granules represent membraneless organelles – biomolecular condensates lacking a membrane and maintained through an intricate
LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent
Dagmar Zweytick1,2
Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved
Endoplasmic reticulum and Golgi stress in microcephaly
Sandrine Passemard1,2, Franck Perez3, Pierre Gressens1,4 and Vincent El Ghouzzi1
Microcephaly is a neurodevelopmental condition characterized by a small brain size associated with intellectual deficiency in most cases and is one of the most frequent clinical sign encountered in neurodevelopmental disorders. It can result from a wide range of environmental insults occurring during pregnancy or postnatally, as well as from various genetic causes and represents a highly heterogeneous condition. However, several lines of evidence highlight a compromised mode of division of the cortical precursor cells during neurogenesis, affecting neural commitment or survival as one of the common mechanisms leading to a limited production of neurons and associated with the most severe forms of congenital microcephaly. In this context, the emergence of the endoplasmic reticulum (ER) and the Golgi apparatus as key guardians of cellular homeostasis, especially through the regulation of proteostasis, has raised the hypothesis that pathological ER and/or Golgi stress could contribute significantly to cortical impairments eliciting microcephaly. In (…)
LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects
Hsin-Wei Liao1,#, Christopher Garris1,#, Christina Pfirschke1, Steffen Rickelt2, Sean Arlauckas1, Marie Siwicki1, Rainer H. Kohler1, Ralph Weissleder1, Vibeke Sundvold-Gjerstad3, Baldur Sveinbjørnsson3,4, Øystein Rekdal3,4 and Mikael J. Pittet1
LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of (...)
Anti-regulatory T cells are natural regulatory effector T cells
Niels Ødum 1
It is well established that the immune system uses regulatory immune-suppressive cells to inhibit and terminate immune reactions and maintain immune balance. In the last decade, Andersen and colleagues have
The impact of endothelial cell death in the brain and its role after stroke: A systematic review
Marietta Zille1, Maulana Ikhsan1, Yun Jiang1,2, Josephine Lampe1,2, Jan Wenzel1,2 and
Markus Schwaninger1,2
INTRODUCTION The brain is a metabolically active organ that consumes about 20% of the total energy of the body [1]. At the same time, it is unable to store significant
Inflammation induced PD-L1-specific T cells
Shamaila Munir1, Mia Thorup Lundsager1, Mia Aabroe Jørgensen1, Morten Hansen1, Trine Hilkjær Petersen2, Charlotte Menne Bonefeld2, Christina Friese1, Özcan Met1,2, Per thor Straten1,2 and Mads Hald Andersen1,2,3
PD-L1-specific T cells are a natural part of the T-cell repertoire in humans. Hence, we have previously described spontaneous CD8+ and CD4+ T-cell reactivity against PD-L1 in the peripheral blood of patients with various cancers as well as in healthy donors. It is well described that the expression of the PD-L1 protein is introduced in cells by pro-inflammatory cytokines, e.g. IFN-γ. In the current study, we were able to directly link inflammation with PD-L1-specific T cells by showing that inflammatory mediators such as IFN-γ generate measurable numbers of PD-L1-specific T cells in human PBMCs as well as in in vivo models. These PD-L1-specific T cells can vigorously modulate the cell compartments of the local environment. PD-L1-specific T cells may be important for immune homeostasis by sustaining the ongoing inflammatory response by the suppression of regulatory cell function both (…)
Stress granules regulate paraspeckles: RNP granule continuum at work
Haiyan An1 and Tatyana A. Shelkovnikova1
Eukaryotic cells contain a variety of large, multicomponent RNA-protein complexes termed ribonucleoprotein (RNP) granules. RNP granules represent membraneless organelles – biomolecular condensates lacking a membrane and maintained through an intricate
LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent
Dagmar Zweytick1,2
Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved
Endoplasmic reticulum and Golgi stress in microcephaly
Sandrine Passemard1,2, Franck Perez3, Pierre Gressens1,4 and Vincent El Ghouzzi1
Microcephaly is a neurodevelopmental condition characterized by a small brain size associated with intellectual deficiency in most cases and is one of the most frequent clinical sign encountered in neurodevelopmental disorders. It can result from a wide range of environmental insults occurring during pregnancy or postnatally, as well as from various genetic causes and represents a highly heterogeneous condition. However, several lines of evidence highlight a compromised mode of division of the cortical precursor cells during neurogenesis, affecting neural commitment or survival as one of the common mechanisms leading to a limited production of neurons and associated with the most severe forms of congenital microcephaly. In this context, the emergence of the endoplasmic reticulum (ER) and the Golgi apparatus as key guardians of cellular homeostasis, especially through the regulation of proteostasis, has raised the hypothesis that pathological ER and/or Golgi stress could contribute significantly to cortical impairments eliciting microcephaly. In (…)
LTX-315 sequentially promotes lymphocyte-independent and lymphocyte-dependent antitumor effects
Hsin-Wei Liao1,#, Christopher Garris1,#, Christina Pfirschke1, Steffen Rickelt2, Sean Arlauckas1, Marie Siwicki1, Rainer H. Kohler1, Ralph Weissleder1, Vibeke Sundvold-Gjerstad3, Baldur Sveinbjørnsson3,4, Øystein Rekdal3,4 and Mikael J. Pittet1
LTX-315 is an oncolytic peptide that has antitumor efficacy in mice grafted with various tumor cell lines and is currently being tested in phase II clinical trials. Here we aimed to further evaluate LTX-315 in conditional genetic mouse models of cancer that typically resist current treatment options and to better understand the drug’s mode of action in vivo. We report LTX-315 mediates profound antitumor effects against Braf- and Pten-driven melanoma and delays the progression of Kras- and P53-driven soft tissue sarcoma in mice. Additionally, we show in melanoma that LTX-315 triggers two sequential phases of antitumor response. The first phase of response, which begins within minutes of drug delivery into tumors, is defined by disrupted tumor vasculature and decreased tumor burden and occurs independently of (...)
Anti-regulatory T cells are natural regulatory effector T cells
Niels Ødum 1
It is well established that the immune system uses regulatory immune-suppressive cells to inhibit and terminate immune reactions and maintain immune balance. In the last decade, Andersen and colleagues have
The role of epigenetics in hypothalamic energy balance control: implications for obesity
Arnaud Obri1 and Marc Claret1,2
INTRODUCTION The prevalence of obesity continues to increase worldwide. This trend is of concern because of its dramatic economic impact, concomitant decreased lifespan and increased comorbidities, such as hypertension, cardiovascular
Remodeling of mitochondrial morphology and function: an emerging hallmark of cellular reprogramming
Anuj Rastogi1, Piyush Joshi2,3, Ela Contreras1 and Vivian Gama1,2,3,4
Research in the stem cell field has traditionally focused on understanding key transcriptional factors that provide pluripotent cell identity. However, much less is known about other critical non-transcriptional signaling networks that govern stem cell identity. Although we continue to gain critical insights into the mechanisms underlying mitochondrial morphology and function during cellular reprogramming – the process of reverting the fate of a differentiated cell into a stem cell, many uncertainties remain. Recent studies suggest an emerging landscape in which mitochondrial morphology and function have an active role in maintaining and regulating changes in cell identity. In this review, we will focus on these emerging concepts as crucial modulators of cellular reprogramming. Recognition of the widespread applicability of these concepts will increase our understanding of the mitochondrial mechanisms involved in cell identity, cell fate and disease.
The sensing of mitochondrial DAMPs by non-immune cells
Aida Rodríguez-Nuevo1,2,3 and Antonio Zorzano1,2,3
MITOCHONDRIA ARE IMMUNOGENIC ORGANELLES The efficiency of the innate immune system is determined by the capacity of distinct cell types to discriminate self from non-self structures. The dysregulation of this
Biology and clinical relevance of EpCAM
Laura Keller1,§, Stefan Werner1,§ and Klaus Pantel1
INTRODUCTION The EpCAM protein was discovered almost 40 years ago as a major epithelial carcinoma antigen by M. Herlyn and colleagues, as a result of its property to generate monoclonal
Recent progress in the role of autophagy in neurological diseases
Tian Meng1,#, Shiyin Lin1,#, Haixia Zhuang1, Haofeng Huang2, Zhengjie He1, Yongquan Hu1, Qing Gong3 and Du Feng1
Autophagy (here refers to macroautophagy) is a catabolic pathway by which large protein aggregates and damaged organelles are first sequestered into a double-membraned structure called autophagosome and then delivered to lysosome for destruction. Recently, tremendous progress has been made to elucidate the molecular mechanism and functions of this essential cellular metabolic process. In addition to being either a rubbish clearing system or a cellular surviving program in response to different stresses, autophagy plays important roles in a large number of pathophysiological conditions, such as cancer, diabetes, and especially neurodegenerative disorders. Here we review recent progress in the role of autophagy in neurological diseases and discuss how dysregulation of autophagy initiation, autophagosome formation, maturation, and/or autophagosome-lysosomal fusion step contributes to the pathogenesis of these disorders in the nervous system.
Tissue-resident memory T cells orchestrate tumour-immune equilibrium
Simone L. Park1, Laura K. Mackay1, Jason Waithman2 and Thomas Gebhardt1
EPICUTANEOUS MELANOMA INOCULATION: A MODEL OF TUMOUR-IMMUNE EQUILIBRIUM In order to study immune responses to skin cancer, B16 melanoma cells have traditionally been grafted to mice via intradermal or subcutaneous
Constitutional Mosaic Epimutations – a hidden cause of cancer?
Per E. Lønning1,2, Hans P. Eikesdal1,2, Inger M. Løes1,2 and Stian Knappskog1,2
Silencing of tumor suppressor genes by promoter hypermethylation is a key mechanism to facilitate cancer progression in many malignancies. While promoter hypermethylation can occur at later stages of the carcinogenesis process, constitutional methylation of key tumor suppressors may be an initiating event whereby cancer is started. Constitutional BRCA1 methylation due to cis-acting germline genetic variants is associated with a high risk of breast and ovarian cancer. However, this seems to be a rare event, restricted to a very limited number of families. In contrast, mosaic constitutional BRCA1 methylation is detected in 4-7% of newborn females without germline BRCA1 mutations. While the cause of such methylation is poorly understood, mosaic normal tissue BRCA1 methylation is associated with a 2-3 fold increased risk of high-grade serous ovarian cancer (HGSOC). As such, BRCA1 methylation may be the cause of a significant number of ovarian cancers. Given the molecular similarities between HGSOC and basal-like breast cancer, the (...)
LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent
Dagmar Zweytick1,2
Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved
Anti-regulatory T cells are natural regulatory effector T cells
Niels Ødum 1
It is well established that the immune system uses regulatory immune-suppressive cells to inhibit and terminate immune reactions and maintain immune balance. In the last decade, Andersen and colleagues have
The targeting of tumor-associated macrophages by vaccination
Mads Hald Andersen1,2,3
Immune suppressive myeloid cells include a heterogenous population of cells that include tumor-associated macrophages (TAMs). TAMs are major players in inducing the immunosuppressive microenvironment associated with many tumors. These lesions
Mitochondrial stress delays tumorigenesis in a Li-Fraumeni syndrome mouse model
Matthew P. Donnelly1, Jie Li1 and Paul M. Hwang1
As a prominent hub of metabolic activity, the mitochondrion can initiate retrograde signaling in response to bioenergetic stress that is important for various adaptive changes including cell cycle regulation [1][2].
Mitochondria organize the cellular proteostatic response and promote cellular senescence
Yanjun Li1, Lei Liu2, Yushan Zhu1 and Quan Chen1,2
Timely disposal and degradation of misfolded proteins and their aggregates is critical for cellular proteostasis and the well-being of a cell. During evolution, cells have acquired a sophisticated system to
Could de-stressing the brain be the solution for long-term weight loss?
Florian Seyfried1 and Mohammed K. Hankir2
INTRODUCTION One just needs to take a look at a typical vending machine (often found in hospitals) to appreciate what has happened to our food and drink. The relatively sudden