Evangelos Giampazolias - Academia.edu (original) (raw)

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Papers by Evangelos Giampazolias

Journal for ImmunoTherapy of Cancer

Type 1 conventional dendritic cells (cDC1) play a critical role in priming anticancer cytotoxic C... more Type 1 conventional dendritic cells (cDC1) play a critical role in priming anticancer cytotoxic CD8+ T cells. DNGR-1 (a.k.a. CLEC9A) is a cDC1 receptor that binds to F-actin exposed on necrotic cancer and normal cells. DNGR-1 signaling enhances cross-presentation of dead-cell associated antigens, including tumor antigens. We have recently shown that secreted gelsolin (sGSN), a plasma protein, competes with DNGR-1 for binding to dead cell-exposed F-actin and dampens anticancer immunity. Here, we investigated the effects of loss of sGSN on various anticancer therapies that are thought to induce cell death and provoke an immune response to cancer. We compared WT (wildtype) with Rag1–/–, Batf3–/–, Clec9agfp/gfp, sGsn–/– or sGsn–/– Clec9agfp/gfp mice implanted with transplantable tumor cell lines, including MCA-205 fibrosarcoma, 5555 BrafV600E melanoma and B16-F10 LifeAct (LA)-ovalbumin (OVA)-mCherry melanoma. Tumor-bearing mice were treated with (1) doxorubicin (intratumoral) chemothera...

Cell, 2021

Highlights d Secreted gelsolin (sGSN) inhibits DNGR-1 binding to F-actin d sGSN dampens DNGR-1-de... more Highlights d Secreted gelsolin (sGSN) inhibits DNGR-1 binding to F-actin d sGSN dampens DNGR-1-dependent cross-presentation of dead cell-associated antigens d sGSN impairs DNGR-1-dependent cDC1-mediated antitumor immunity d Low sGSN expression and mutations in FABPs correlate with cancer patient survival

Nature Communications, 2020

The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements.... more The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammato...

Immunity, 2019

Highlights d Macrophages express Amphiregulin upon tissue damage d Amphiregulin activates integri... more Highlights d Macrophages express Amphiregulin upon tissue damage d Amphiregulin activates integrin-a V complexes on pericytes d Integrin-a V-activated TGF-b induces pericyte into myofibroblast differentiation d Myofibroblast-derived collagen contributes to wound healing

FEBS Journal, 2015

Mitochondria have been traditionally viewed as the powerhouse of the cell due to their major role... more Mitochondria have been traditionally viewed as the powerhouse of the cell due to their major role in the generation of ATP. More recently, mitochondria have also been demonstrated to have key roles in a variety of other processes such as apoptotic cell death and inflammation. Here we review the different ways in which mitochondrial functions impact on cancer. While cancer is comprised of diverse types, distinct hallmarks have been defined that are applicable to most cancer types. We provide an overview of how mitochondria impact on specific hallmarks; these include evasion of cell death, deregulated bioenergetics, genome instability, tumour promoting inflammation and metastasis. In addition to discussing the underlying mitochondrial roles in each of these processes, we also highlight the considerable promise of targeting mitochondrial functions in order to improve cancer treatment.

Nature cell biology, 2017

Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochon... more Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the downregulation of inhibitor of apoptosis proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent ...

Current biology : CB, Jan 18, 2017

The individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, ... more The individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large, bulky pseudopods with dynamic actin bursts. Despite assuming an elongated shape usually as...

Nature Communications, 2016

Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to e... more Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject to tight control by Bcl-2 family proteins. We have developed a powerful new technique to investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression of pro- and anti-apoptotic Bcl-2 proteins to engineer Bcl-2 addiction. On addition of Bcl-2 targeting BH3 mimetics, mito-primed cells undergo apoptosis in a rapid and synchronous manner. Using this method we have comprehensively surveyed the efficacy of BH3 mimetic compounds, identifying potent and specific MCL-1 inhibitors. Furthermore, by combining different pro- and anti-apoptotic Bcl-2 pairings together with CRISPR/Cas9-based genome editing, we find that tBID and PUMA can preferentially kill in a BAK-dependent manner. In summary, mito-priming represents a facile and robust means to trigger mitochondrial apoptosis.

Molecular Cell, 2015

Highlights d MOMP can occur in a minority of mitochondria d Minority MOMP triggers caspase activi... more Highlights d MOMP can occur in a minority of mitochondria d Minority MOMP triggers caspase activity but fails to kill cells d Minority MOMP-induced caspase activity causes DNA damage and genomic instability d Minority MOMP promotes cellular transformation and tumorigenesis