Table of contents

Volume 2, Issue 10, pp. 242 - 281, October 2018

Issue cover
Cover: This month in Cell Stress: Mitochondrial stress management and astrocytes in energy homeostasis. Image depicts a collage of immunofluorescence pictures of astrocytes. Credit: Jason Snyder (image "GFAP-driven thymidine kinase in a mouse brain - color combo2") and GerryShaw (image "Astrocyte5.jpg";, licensed under a CC BY-SA 3.0 license. Image modified by Cell Stress. Enlarge issue cover

News and Thoughts

Base editors: a powerful tool for generating animal models of human diseases

Zongyang Lu and Xingxu Huang

page 242-245 | 10.15698/cst2018.10.156 | Full text | PDF | Abstract

Myriads of genetic mutations, including base substitutions, deletions, and insertions as well as chromosome structural variations, have been detected in many human diseases. Although current combination of genomics and bioinformatics has contributed greatly to understanding the genetics of these disorders, it remains challenging to ensure the causal functions of each mutation, and then to further investigate the underlying mechanism and to develop therapeutic strategies. Animal models generated by genome engineering are the key to address these issues. In this review, we will first revisit the limitation of conventional gene editing tools and mouse models generated in the past. We will then introduce a novel tool, base editors (BEs), which present a new promising approach to establish pathogenically relevant animal models. Finally, we will discuss the application of BEs in non-human primates and share our perspectives on future development of base-editing techniques.


Astrocytes, emerging stars of energy homeostasis

Simonetta Camandola

page 246-252 | 10.15698/cst2018.10.157 | Full text | PDF | Abstract

Astrocytes have historically been considered structural supporting cells for neurons. Thanks to new molecular tools, allowing specific cell ablation or over-expression of genes, new unexpected astrocytic functions have recently been unveiled. This review focus on emerging groundbreaking findings showing that hypothalamic astrocytes are pivotal for the regulation of whole body energy homeostasis. Hypothalamic astrocytes sense glucose and fatty acids, and express receptors for several peripheral hormones such as leptin and insulin. Furthermore, they display striking sexual dimorphism which may account, at least partially, for gender specific differences in energy homeostasis. Metabolic alterations have been shown to influence the initiation and progression of many neurodegenerative disorders. A better understanding of the roles and interplay between the different brain cells in regulating energy homeostasis could help develop new therapeutic strategies to prevent or cure neurodegenerative disorders.


Mitochondrial stress management: a dynamic journey

Miriam Valera-Alberni and Carles Canto

page 253-274 | 10.15698/cst2018.10.158 | Full text | PDF | Abstract

Mitochondria undergo continuous challenges in the course of their life, from their generation to their degradation. These challenges include the management of reactive oxygen species, the proper assembly of mitochondrial respiratory complexes and the need to balance potential mutations in the mitochondrial DNA. The detection of damage and the ability to keep it under control is critical to fine-tune mitochondrial function to the organismal energy needs. In this review, we will analyze the multiple mechanisms that safeguard mitochondrial function in light of in crescendo damage. This sequence of events will include initial defense against excessive reactive oxygen species production, compensation mechanisms by the unfolded protein response (UPRmt), mitochondrial dynamics and elimination by mitophagy.


Intravital imaging tumor screen used to identify novel metastasis-blocking therapeutic targets

Konstantin Stoletov, Lian Willetts, Perrin H. Beatty and John D. Lewis

page 275-278 | 10.15698/cst2018.10.159 | Full text | PDF | Abstract

Cancer cell motility is a key driver of metastasis. Although the intravasation of cancer cells into the blood stream is highly dependent on their motility and metastatic dissemination is the primary cause of cancer related deaths, current therapeutic strategies do not target the genes and proteins that are essential for cell motility. A primary reason for this is because the identification of cell motility-related genes that are relevant in vivo requires the visualization of metastatic lesions forming in an appropriate in vivo model. The cancer research community has lacked an in vivo and intravital metastatic cancer model that could be imaged as motility developed, in real-time. To address this, we developed a novel quantitative in vivo screening platform based on intravital imaging in shell-less ex ovo chick embryos. We applied this imaging approach to screen a human genome-wide short hairpin RNA library (shRNA) versus the highly motile head and neck cancer cells (HEp3 cell line) introduced into the chorioallantoic membrane (CAM) of chick embryos and identified multiple novel in vivo cancer cell motility-associated genes. When the expression of several of the identified genes was inhibited in the HEp3 tumors, we observed a nearly total block of spontaneous cancer metastasis.

Therapeutic anti-tumor immunity directed against neo-epitopes by intratumor delivery of mRNA encoding MLKL

Lien Van Hoecke and Xavier Saelens

page 279-281 | 10.15698/cst2018.10.160 | Full text | PDF | Abstract

In recent years, it has become increasingly clear that successful treatment of cancer is possible through the induction of anti-tumor immunity combined with killing of tumor cells. One approach to reach this is to apply cancer vaccines comprising tumor-specific antigens to elicit cellular immunity and chemotherapy to reduce the tumor mass. However, in some cases the dying tumor cell can itself become the vaccine, in particular when the antineoplastic treatment induces so called immunogenic cell death. Immunogenic cell death is characterized by the exposure of damage associated molecular patterns (DAMPs). DAMPs are recognized by innate immune cells which subsequently can prime effector T cell responses against tumor-specific antigens. Unfortunately, many tumors resist exogenous immunogenic cell death stimuli through acquired mutations in cell death signaling pathways. In our recent study (Nat Commun, 9(1):3417), we aimed to overcome these issues through the direct delivery in tumor cells of hypo-inflammatory messenger RNA (mRNA) that codes for mixed lineage kinase domain-like (MLKL) protein, an executioner of necroptosis. This mRNA-based treatment resulted in the potent induction of systemic cellular anti-tumor immune responses that were associated with the regression of the treated as well as distal non-treated tumor cells, as demonstrated in mouse models of transplantable tumors.

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