Table of contents

Volume 2, Issue 12, pp. 332 - 367, December 2018

Issue cover
Cover: This month in Cell Stress: Nutrient stress in pancreatic cancer. Image depicts sections of a histological staining showing a putative adenocarcinoma of the pancreas, which is particularly difficult to diagnose based on histological images alone. Image by Ed Uthman, licensed under a CC BY 2.0 license. Image modified by Cell Stress. The cover is published under the CC BY 4.0 license. Enlarge issue cover


The role of metabolic adaptation to nutrient stress in pancreatic cancer

Abhishek Derle, Maria Chiara De Santis, Luca Gozzelino, Edoardo Ratto and Miriam Martini

page 332-339 | 10.15698/cst2018.12.166 | Full text | PDF | Abstract

Pancreatic cancer is the fourth most common cause of cancer-related mortality, with a dismal prognosis that has changed little over the past few decades. Despite extensive efforts in understanding the oncogenetics of this pathology, pancreatic cancer remained largely elusive. One of the main characteristics of pancreatic cancer is the reduced level of oxygen and nutrient perfusion, caused by the new matrix formation, through the activation of stromal cells (desmoplasia). This stromal reaction leads to metabolic adaptations in surviving tumor cells in order to cope with these challenging conditions. The oncogenic signaling driven by KRAS mutation is necessary to fuel pancreatic tumors by activating key metabolic processes, including enhanced glycolysis and glutamine consumption. Here we review our current understanding of the pancreatic cancer metabolism as well as discuss recent work pointing to the importance of various metabolic strategies as well as autophagy and macropinocytosis as critical nutrient supply pathways. The elucidation of these metabolic networks may highlight new opportunities to further develop novel therapeutic strategies.

Systemic signalling and local effectors in developmental stability, body symmetry, and size

Sergio Juarez-Carreño, Javier Morante and Maria Dominguez

page 340-361 | 10.15698/cst2018.12.167 | Full text | PDF | Abstract

Symmetric growth and the origins of fluctuating asymmetry are unresolved phenomena of biology. Small, and sometimes noticeable, deviations from perfect bilateral symmetry reflect the vulnerability of development to perturbations. The degree of asymmetry is related to the magnitude of the perturbations and the ability of an individual to cope with them. As the left and right sides of an individual were presumed to be genetically identical, deviations of symmetry were traditionally attributed to non-genetic effects such as environmental and developmental noise. In this review, we draw attention to other possible sources of variability, especially to somatic mutations and transposons. Mutations are a major source of phenotypic variability and recent genomic data have highlighted somatic mutations as ubiquitous, even in phenotypically normal individuals. We discuss the importance of factors that are responsible for buffering and stabilizing the genome and for maintaining size robustness and quality through elimination of less-fit or damaged cells. However, the important question that arises from these studies is whether this self-correcting capacity and intrinsic organ size controls are sufficient to explain how symmetric structures can reach an identical size and shape. Indeed, recent discoveries in the fruit fly have uncovered a conserved hormone of the insulin/IGF/relaxin family, Dilp8, that is responsible for stabilizing body size and symmetry in the face of growth perturbations. Dilp8 alarm signals periphery growth status to the brain, where it acts on its receptor Lgr3. Loss of Dilp8-Lgr3 signaling renders flies incapable of detecting growth perturbations and thus maintaining a stable size and symmetry. These findings help to understand how size and symmetry of somatic tissues remain undeterred in noisy environments, after injury or illnesses, and in the presence of accumulated somatic mutations.


Full antagonist of the IL-7 receptor suppresses chronic inflammation in non-human primate models by controlling antigen-specific memory T cells

Lyssia Belarif, Bernard Vanhove and Nicolas Poirier

page 362-364 | 10.15698/cst2018.12.169 | Full text | PDF | Abstract

Targeting the expansion of pathogenic memory immune cells is a promising therapeutic strategy to prevent chronic autoimmune attacks. Interleukin 7 (IL-7) is a limiting and potent cytokine produced by epithelial and stromal cells sustaining T-lymphocytes development, homeostasis and cell metabolism. Almost all conventional mature T lymphocytes express the IL-7 receptor (IL-7R), with the exception for naturally-occurring regulatory T-cells (Treg), constituting a rare opportunity to selectively strangle pathogenic effectors while preserving crucial natural regulators. In our recent study, we reported that therapeutic efficacy of antagonist anti- IL-7Rα mAbs in a non-human primate model of memory T cell-induced chronic inflammation depends on recognition of an epitope overlapping the IL-7 binding domain (site 1) and the receptor heterodimerization region (site-2b) (Nat Commun, 9(1):4483). We found that “site-1-only” mAbs prevented IL-7-induced JAK/STAT signaling but induced PI3K and Erk signaling and lacked efficacy in vivo, whereas “site-1 + 2b” mAbs were fully antagonist and demonstrated potent activity to control skin inflammation on the long term. The mechanism of action comprised the neutralization of IFN-γ producing antigen-specific memory T cells, without inducing lymphopenia or polyclonal T-cell functional or metabolic defects as generally observed previously in rodents.

TRIM16 employs NRF2, ubiquitin system and aggrephagy for safe disposal of stress-induced misfolded proteins

Kautilya Kumar Jena, Subhash Mehto, Srinivasa Prasad Kolapalli, Parej Nath, Swati Chauhan and Santosh Chauhan

page 365-367 | 10.15698/cst2018.12.169 | Full text | PDF | Abstract

The cellular stresses, genetic mutations, and environmental factors can critically affect the protein quality control checkpoints resulting in protein misfolding. Molecular chaperones play a crucial role in maintaining the healthy proteome by refolding the misfolded proteins into the native functional conformations. However, if they fail to refold the misfolded proteins into the native state, they are targeted by proteolytic systems for degradation. If the misfolded protein numbers increase more than what a cell can resolve, they get converted protein aggregates/inclusion bodies. The inclusion bodies are less cytotoxic than misfolded proteins. The enhanced production of misfolded proteins and protein aggregates are linked to several diseases collectively termed proteinopathies, which includes several neurodegenerative disorders. The understanding of molecular mechanisms that regulate the turnover of protein aggregates will pave path for therapeutic interventions of proteinopathies. In a recent report, we showed that a tripartite motif (TRIM) family protein, TRIM16 streamlines the process of protein aggregates turnover by regulating the NRF2-p62 axis and autophagy.

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