Volume 3 (2019)

Gold Nanoparticles sensitize pancreatic cancer cells to gemcitabine

Yanyan Huai¹, Yushan Zhang¹, Xunhao Xiong¹, Shamik Das², Resham Bhattacharya² and Priyabrata Mukherjee^1,2

INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. The mortality rate closely parallels that of incidence [1][2]. The current standard of care for advanced stage PDAC patients includes

Unraveling the molecular principles by which ceramides commit cells to death

Shashank Dadsena¹, Dina G. Hassan¹ and Joost C.M. Holthuis¹

EMERGENCE OF CERAMIDES AS TUMOR SUPPRESSOR LIPIDS Sphingolipids are unusually versatile membrane components that participate in mechanical stability, signaling, and molecular sorting. As the path to their production is paved

Immunosurveillance of cancer cell stress

Seila Lorenzo-Herrero^1-3, Christian Sordo-Bahamonde^1-3, Segundo González^1-3 and Alejandro López-Soto^1-3

Cancer development is tightly controlled by effector immune responses that recognize and eliminate malignantly transformed cells. Nonetheless, certain immune subsets, such as tumor-associated macrophages, have been described to promote tumor growth, unraveling a double-edge role of the immune system in cancer. Cell stress can modulate the crosstalk between immune cells and tumor cells, reshaping tumor immunogenicity and/or immune function and phenotype. Infiltrating immune cells are exposed to the challenging conditions typically present in the tumor microenvironment. In return, the myriad of signaling pathways activated in response to stress conditions may tip the balance toward stimulation of antitumor responses or immune-mediated tumor progression. Here, we explore how distinct situations of cellular stress influence innate and adaptive immunity and the consequent impact on cancer establishment and progression.

Myelopoiesis, metabolism and therapy: a crucial crossroads in cancer progression

Antonio Sica^1,2, Valentina Guarneri^3,4 and Alessandra Gennari⁵

INTRODUCTION The bone marrow (BM) is a primary lymphoid organ that hosts hematopoietic progenitors and presides over hematopoiesis, which is defined as the production of all types of blood cells.

Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity

Maite Alvarez^1,2, Itziar Otano^1,2, Luna Minute^1,2, Maria Carmen Ochoa^1,2,3, Elisabeth Perez-Ruiz^1,4, Ignacio Melero^1,2,3,5,6 and Pedro Berraondo^1,2,3

Inhibitory checkpoint blockade (ICB) immunotherapy has produced very significant advances in the fight against cancer (Figure 1). The synergistic combination of PD-1 and CTLA-4 blockade therapy has been successfully used

Immunometabolic cross-talk in the inflamed heart

Federica M. Marelli-Berg^1,3 and Dunja Aksentijevic^2,3

Inflammatory processes underlie many diseases associated with injury of the heart muscle, including conditions without an obvious inflammatory pathogenic component such as hypertensive and diabetic cardiomyopathy. Persistence of cardiac inflammation can cause irreversible structural and functional deficits. Some are induced by direct damage of the heart muscle by cellular and soluble mediators but also by metabolic adaptations sustained by the inflammatory microenvironment. It is well established that both cardiomyocytes and immune cells undergo metabolic reprogramming in the site of inflammation, which allow them to deal with decreased availability of nutrients and oxygen. However, like in cancer, competition for nutrients and increased production of signalling metabolites such as lactate initiate a metabolic cross-talk between immune cells and cardiomyocytes which, we propose, might tip the balance between resolution of the inflammation versus adverse cardiac remodeling. Here we review our current understanding of the metabolic reprogramming of both heart tissue and immune (...)

The role of epigenetics in hypothalamic energy balance control: implications for obesity

Arnaud Obri¹ and Marc Claret^1,2

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

Stress and catecholamines modulate the bone marrow microenvironment to promote tumorigenesis

Pauline Hanns¹, Anna M. Paczulla¹, Michael Medinger², Martina Konantz¹ and Claudia Lengerke^1,2

High vascularization and locally secreted factors make the bone marrow (BM) microenvironment particularly hospitable for tumor cells and bones to a preferred metastatic site for disseminated cancer cells of different origins. Cancer cell homing and proliferation in the BM are amongst other regulated by complex interactions with BM niche cells (e.g. osteoblasts, endothelial cells and mesenchymal stromal cells (MSCs)), resident hematopoietic stem and progenitor cells (HSPCs) and pro-angiogenic cytokines leading to enhanced BM microvessel densities during malignant progression. Stress and catecholamine neurotransmitters released in response to activation of the sympathetic nervous system (SNS) reportedly modulate various BM cells and may thereby influence cancer progression. Here we review the role of catecholamines during tumorigenesis with particular focus on pro-tumorigenic effects mediated by the BM niche.

Remodeling of mitochondrial morphology and function: an emerging hallmark of cellular reprogramming

Anuj Rastogi¹, Piyush Joshi^2,3, Ela Contreras¹and Vivian Gama^1,2,3,4

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.

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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

Metabolism remodeling in pancreatic ductal adenocarcinoma

Jin-Tao Li¹, Yi-Ping Wang¹, Miao Yin¹ and Qun-Ying Lei^{1, 2}

INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a tumor with early metastatic potential and remarkable resistance to established therapies such as chemotherapy, radiotherapy, and molecular targeted therapy [1]. Given primary localization

LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent

Dagmar Zweytick^1,2

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 Passemard^1,2, Franck Perez³, Pierre Gressens^1,4 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 Liao^1,#, Christopher Garris^1,#, Christina Pfirschke¹, Steffen Rickelt², Sean Arlauckas¹, Marie Siwicki¹, Rainer H. Kohler¹, Ralph Weissleder¹, Vibeke Sundvold-Gjerstad³, Baldur Sveinbjørnsson^3,4, Øystein Rekdal^3,4 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

Stress granules regulate paraspeckles: RNP granule continuum at work

Haiyan An¹ and Tatyana A. Shelkovnikova¹

Metabolism remodeling in pancreatic ductal adenocarcinoma

Jin-Tao Li¹, Yi-Ping Wang¹, Miao Yin¹ and Qun-Ying Lei^{1, 2}

Endoplasmic reticulum and Golgi stress in microcephaly

Sandrine Passemard^1,2, Franck Perez³, Pierre Gressens^1,4 and Vincent El Ghouzzi¹

The impact of endothelial cell death in the brain and its role after stroke: A systematic review

Marietta Zille¹, Maulana Ikhsan¹, Yun Jiang^1,2, Josephine Lampe^1,2, Jan Wenzel^1,2 and
Markus Schwaninger^1,2

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

Acyl-CoA-binding protein (ACBP): the elusive ‘hunger factor’ linking autophagy to food intake

José Manuel Bravo-San Pedro^1-3, Valentina Sica^1-3, Frank Madeo^4,5 and Guido Kroemer^1-3,6-8

Overweight has beaten undernutrition as the most frequent pathological state throughout the world, affecting close to 25% of the adult population. This has severe implications for global health, given that

Unraveling the molecular principles by which ceramides commit cells to death

Shashank Dadsena¹, Dina G. Hassan¹ and Joost C.M. Holthuis¹

Immunosurveillance of cancer cell stress

Seila Lorenzo-Herrero^1-3, Christian Sordo-Bahamonde^1-3, Segundo González^1-3 and Alejandro López-Soto^1-3

Myelopoiesis, metabolism and therapy: a crucial crossroads in cancer progression

Antonio Sica^1,2, Valentina Guarneri^3,4 and Alessandra Gennari⁵

INTRODUCTION The bone marrow (BM) is a primary lymphoid organ that hosts hematopoietic progenitors and presides over hematopoiesis, which is defined as the production of all types of blood cells.

Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity

Maite Alvarez^1,2, Itziar Otano^1,2, Luna Minute^1,2, Maria Carmen Ochoa^1,2,3, Elisabeth Perez-Ruiz^1,4, Ignacio Melero^1,2,3,5,6 and Pedro Berraondo^1,2,3

LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent

Dagmar Zweytick^1,2

Anti-regulatory T cells are natural regulatory effector T cells

Niels Ødum ¹

The targeting of tumor-associated macrophages by vaccination

Mads Hald Andersen^1,2,3

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 Chen^1,2

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