Extracellular Vesicles & Co.: scaring immune cells in the TME since ever.

The health tissue surrounding a solid tumor, namely the tumor microenvironment (TME), is an extremely complex universe of cells, extracellular matrix, and signals of various nature, that support and protect the growth of cancer cells. The interactions taking place between cancer cells and the TME are crucial not only for tumor growth, invasion, and metastasis but they also play a key role in modulating immune system responses to cancer, and vice-versa. Indeed, tumor-infiltrating immune cells (e.

Mitochondrial Transfer as a Strategy for Enhancing Cancer Cell Fitness:Current Insights and Future Directions.

It is now recognized that tumors are not merely masses of transformed cells but are intricately interconnected with healthy cells in the tumor microenvironment (TME), forming complex and heterogeneous structures. Recent studies discovered that cancer cells can steal mitochondria from healthy cells to empower themselves, while reducing the functions of their target organ. Mitochondrial transfer, i.

Migrasomes, new vescicles as Hansel and Gretel white pebbles?

Migrasomes, released by migrating cells, belong to the heterogeneous world of extracellular vesicles (EVs). However, they can be distinguished from all other members of EVs by their size, biorigin and protein cargo. As far as we know, they can play important roles in various communication processes, by mediating the release of signals, such as mRNAs, proteins or damaged mitochondria.

The long non-coding RNA overexpression impacts on acute myeloid leukemia differentiation and mitochondrial dynamics.

Patients with acute myeloid leukemia (AML) carrying high-risk genetic lesions or high residual disease levels after therapy are particularly exposed to the risk of relapse. Here, we identified the long non-coding RNA able to cluster an AML subgroup with peculiar gene signatures linked to hematopoietic cell differentiation and mitochondrial dynamics. silencing triggered hematopoietic commitment in healthy CD34+ cells, whereas in AML cells the pathological undifferentiated state was rescued.

PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism.

Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells.

Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling.

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MB) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB.

Following the Dynamism of the Mitochondrial Network in T Cells.

The dynamism of mitochondria, considered as complex and motile organelles, is brought about by mitochondria ability to undergo cycles of fission and fusion events, whose fine balance determines their morphology in a specific physiological context. A huge body of evidence makes it possible to associate mitochondrial organization to regulation of an increasing number of key cellular processes, such as biosynthetic pathways, oxidative phosphorylation and ATP production, calcium buffering, mtDNA homeostasis, autophagy, and cell death. Here, we review the recently developed imaging methods for studying mitochondrial dynamics, including live-cell imaging, by using mitochondrial-targeted fluorescent proteins.

AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.

Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway. Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability.

Thioridazine requires calcium influx to induce MLL-AF6-rearranged AML cell death.

In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate.

Corrigendum: Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri.

[This corrects the article DOI: 10.3389/fimmu.2020.

Correction: JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri.

"Location, location, and location": according to this mantra, the place where living beings settle has a key impact on the success of their activities; in turn, the living beings can, in many ways, modify their environment. This idea has now become more and more true for T cells. The ability of T cells to recirculate throughout blood or lymph, or to stably reside in certain tissues, turned out to determine immunity to pathogens, and tumors.

JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction.

The Activation-Induced Cell Death (AICD) is a stimulation-dependent form of apoptosis used by the organism to shutdown T-cell response once the source of inflammation has been eliminated, while allowing the generation of immune memory. AICD is thought to progress through the activation of the extrinsic Fas/FasL pathway of cell death, leading to cytochrome-C release through caspase-8 and Bid activation. We recently described that, early upon AICD induction, mitochondria undergo structural alterations, which are required to promote cytochrome-C release and execute cell death.

T lymphocytes against solid malignancies: winning ways to defeat tumours.

In the last decades, a novel field has emerged in the cure of cancer, by boosting the ability of the patient's immune system to recognize and kill tumour cells. Although excellent and encouraging results, exploiting the effect of genetically modified T cells, have been obtained, it is now evident that tumour malignancies can evolve several mechanisms to escape such immune responses, thus continuing their growth in the body. These mechanisms are in part due to tumour cell metabolic or genetic alterations, which can render the target invisible to the immune system or can favour the generation of an extracellular milieu preventing immune cell infiltration or cytotoxicity.

Targeting Drp1 and mitochondrial fission for therapeutic immune modulation.

Mitochondria are dynamic organelles whose processes of fusion and fission are tightly regulated by specialized proteins, known as mitochondria-shaping proteins. Among them, Drp1 is the main pro-fission protein and its activity is tightly regulated to ensure a strict control over mitochondria shape according to the cell needs. In the recent years, mitochondrial dynamics emerged as a new player in the regulation of fundamental processes during T cell life.

Reversible induction of mitophagy by an optogenetic bimodular system.

Autophagy-mediated degradation of mitochondria (mitophagy) is a key process in cellular quality control. Although mitophagy impairment is involved in several patho-physiological conditions, valuable methods to induce mitophagy with low toxicity in vivo are still lacking. Herein, we describe a new optogenetic tool to stimulate mitophagy, based on light-dependent recruitment of pro-autophagy protein AMBRA1 to mitochondrial surface.

AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis.

Regulatory T cells (T) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of T cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation.

Monitoring the Mitochondrial Dynamics in Mammalian Cells.

Mitochondria exist in a dynamic state inside mammalian cells. They undergo processes of fusion and fission to adjust their shape according to the different cell needs. Different proteins tightly regulate these dynamics: Opa-1 and Mitofusin-1 and Mitofusin-2 are the main profusion proteins, while Drp1 and its different receptors (Mff, Fis1, MiD49, MiD51) regulate mitochondrial fission.

AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells.

Therapeutic strategies are needed to protect dopaminergic neurons in Parkinson's disease (PD) patients. Oxidative stress caused by dopamine may play an important role in PD pathogenesis. Selective autophagy of mitochondria (mitophagy), mainly regulated by PINK1 and PARKIN, plays an important role in the maintenance of cell homeostasis.

-nitrosylation drives cell senescence and aging in mammals by controlling mitochondrial dynamics and mitophagy.

-nitrosylation, a prototypic redox-based posttranslational modification, is frequently dysregulated in disease. -nitrosoglutathione reductase (GSNOR) regulates protein -nitrosylation by functioning as a protein denitrosylase. Deficiency of GSNOR results in tumorigenesis and disrupts cellular homeostasis broadly, including metabolic, cardiovascular, and immune function.