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Mitochondrial outer membrane permeabilization (MOMP) is crucial for the cytosolic accumulation of mitochondrial DNA (mtDNA) species that are required to jumpstart innate and adaptive immunity. Recent data reported by Ghosh et al. suggest that tumor protein p53 regulates MOMP-dependent type I interferon (IFN) production, not only via MOMP-promoting effects, but also by directing mtDNA-degrading exonucleases to proteasomal processing. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress can stimulate calreticulin (CALR) presentation on the cell surface, promoting the phagocytic uptake of stressed cells by myeloid cells. Recent findings from Wattrus et al. demonstrate that zebrafish and mouse embryonic macrophages engulf CALR-exposing nascent hematopoietic stem cells to ensure the selective survival of stem cells apt for adult hematopoiesis. [ABSTRACT FROM AUTHOR]

Deregulated WNT signaling has been shown to favor malignant transformation, tumor progression, and resistance to conventional cancer therapy in a variety of preclinical and clinical settings. Accumulating evidence suggests that aberrant WNT signaling may also subvert cancer immunosurveillance, hence promoting immunoevasion and resistance to multiple immunotherapeutics, including immune checkpoint blockers. Here, we discuss the molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance and present potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy. Highlights Canonical WNT signaling plays a central role in embryogenesis, tissue homeostasis, and wound repair. Deregulated WNT signaling is involved in virtually all stages of oncogenesis. Impaired anticancer immunity as a result of aberrant WNT signaling is emerging as a key contributor to tumor progression and resistance to treatment. Activation of canonical WNT signaling hampers T cell-mediated anticancer immune responses by multiple mechanisms including immune exclusion. [ABSTRACT FROM AUTHOR]

Unscheduled tetraploidy is a metastable state that rapidly evolves into aneuploidy. Recent findings reported by Gemble et al. demonstrate that freshly formed tetraploid cells fail to accumulate the required amounts of DNA replication factors during the first G 1 phase after whole-genome duplication (WGD), culminating in genetic instability in the subsequent S phase and extensive karyotypic alterations. [ABSTRACT FROM AUTHOR]

Although somatic KRAS mutations are common in human tumors, no inhibitor of mutant KRAS was clinically available until recently. Canon and colleagues describe the ability of a clinically available KRASG12C inhibitor to drive immunogenic cancer cell death, thus constituting a promising combinatorial partner for immune checkpoint blockers. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are widely used for the management of disease- or therapy-related complications in cancer patients. Recent data indicate that activation of GC receptors (GRs) precipitates breast cancer progression by favoring metastatic dissemination and cell survival at distant sites. These findings call for the re-evaluation of GC usage in patients with cancer. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a recent Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. [ABSTRACT FROM AUTHOR]

The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological “side” effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. [ABSTRACT FROM AUTHOR]

Large BAX/BAK pores that form during apoptosis enable mitochondrial nucleoids to access the cytosol, potentially leading to inflammatory signaling via CGAS. Under physiological conditions, however, BAX/BAK-dependent caspase activation rapidly dismantles dying cells to prevent inflammatory responses. BAX and BAK operate at the interface between apoptotic signaling and innate immunity control. [ABSTRACT FROM AUTHOR]

Two recent genomic studies suggest that a large fraction of human tumors evolves in the presence of limited negative selection against somatic mutations. In this context, specific genetic defects enable the establishment of a hypermutant state that may constitute a target for immunotherapeutic interventions. [ABSTRACT FROM AUTHOR]

Demaria and colleagues have recently identified three prime repair exonuclease 1 (TREX1) as a key determinant for the limited immunogenicity of cancer cells responding to single high-dose radiation. TREX1 stands out as a promising target for the development of novel strategies to boost anticancer immune responses driven by radiation therapy (RT). [ABSTRACT FROM AUTHOR]

Two resource articles recently published in Cell demonstrate that the elevated phenotypic complexity of the immune infiltrate in human lung adenocarcinomas and renal cell carcinomas can be reliably dissected with mass cytometry. These findings may pave the way to a new era of precision cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Highlights: [•] Uncontrolled inflammation exacerbates tissue damage in several pathological settings. [•] Chronic inflammatory conditions promote multiple human diseases including cancer. [•] The immune system also eliminates damaged – and hence potentially dangerous – cells. [•] Immunosurveillance plays a major role in the maintenance of tissue homeostasis. [Copyright &y& Elsevier]

Summary: Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including – but not limited to – cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes. [ABSTRACT FROM AUTHOR]

Autophagy is an evolutionarily conserved catabolic pathway that is involved in numerous physiological processes and in multiple pathological conditions including cancer. Autophagy is regulated by an intricate network of signaling cascades that have not yet been entirely disentangled. Accumulating evidence indicates that p53, the best-characterized human tumor suppressor protein, can modulate autophagy in a dual fashion, depending on its subcellular localization. On the one hand, p53 functions as a nuclear transcription factor and transactivates proapoptotic, cell cycle-arresting and proautophagic genes. On the other hand, cytoplasmic p53 can operate at mitochondria to promote cell death and can repress autophagy via poorly characterized mechanisms. This review focuses on the recently discovered function of p53 as a master regulator of autophagy. [Copyright &y& Elsevier]

Abstract: Mitochondria are required for cellular survival, yet can also orchestrate cell death. The peculiar biochemical properties of these organelles, which are intimately linked to their compartmentalized ultrastructure, provide an optimal microenvironment for multiple biosynthetic and bioenergetic pathways. Most intracellular ATP is generated by mitochondrial respiration, which also represents the most relevant source of intracellular reactive oxygen species. Mitochondria participate in a plethora of anabolic pathways, including cholesterol, cardiolipin, heme and nucleotide biosynthesis. Moreover, mitochondria integrate numerous pro-survival and pro-death signals, thereby exerting a decisive control over several biochemical cascades leading to cell death, in particular the intrinsic pathway of apoptosis. Therefore, it is not surprising that cancer cells often manifest the deregulation of one or several mitochondrial functions. The six classical hallmarks of cancer (i.e., limitless replication, self-provision of proliferative stimuli, insensitivity to antiproliferative signals, disabled apoptosis, sustained angiogenesis, invasiveness/metastatic potential), as well as other common features of tumors (i.e., avoidance of the immune response, enhanced anabolic metabolism, disabled autophagy) may directly or indirectly implicate deregulated mitochondria. In this review, we discuss several mechanisms by which mitochondria can contribute to malignant transformation and tumor progression. [Copyright &y& Elsevier]

Autophagy not only constitutes a robust barrier against malignant transformation at the cell-intrinsic level, but also contributes to the organismal control of potentially oncogenic cells. Recent data provide molecular insights into the mechanisms whereby oncogene hyperactivation induces autophagy to establish a permanent proliferative arrest commonly known as cellular senescence. [ABSTRACT FROM AUTHOR]

Abstract: Autophagy constitutes one of the major responses to stress in eukaryotic cells, and is regulated by a complex network of signaling cascades. Not surprisingly, autophagy is implicated in multiple pathological processes, including infection by pathogens, inflammatory bowel disease, neurodegeneration and cancer. Both oncogenesis and tumor survival are influenced by perturbations of the molecular machinery that controls autophagy. Numerous oncoproteins, including phosphatidylinositol 3-kinase, Akt1 and anti-apoptotic members of the Bcl-2 family suppress autophagy. Conversely, several tumor suppressor proteins (e.g., Atg4c; beclin 1; Bif-1; BH3-only proteins; death-associated protein kinase 1; LKB1/STK11; PTEN; UVRAG) promote the autophagic pathway. This does not entirely apply to p53, one of the most important tumor suppressor proteins, which regulates autophagy in an ambiguous fashion, depending on its subcellular localization. Irrespective of the controversial role of p53, basal levels of autophagy appear to inhibit tumor development. On the contrary, chemotherapy- and metabolic stress-induced activation of the autophagic pathway reportedly contribute to the survival of formed tumors, thereby favoring resistance. In this context, autophagy inhibition would represent a major therapeutic target for chemosensitization. Here, we will review the current knowledge on the dual role of autophagy as an anti- and pro-tumor mechanism. [Copyright &y& Elsevier]

Abstract: Mitochondrial membrane permeabilization (MMP) is commonly regarded as the “point-of-no-return” in the cascade of events that delineate the intrinsic pathway of apoptosis. MMP leads to the functional impairment of mitochondria and to the release into the cytosol of toxic proteins that are normally confined within the mitochondrial intermembrane space. These include direct activators of caspases and caspase-independent effectors of the cell death program. MMP has been implicated in a plethora of pathophysiological settings. In particular, MMP contributes to both the immediate and delayed phases of cell loss that follow acute neuronal injury by ischemia/reperfusion or trauma. Although preventing MMP a priori would be the most desirable therapeutic choice, prophylactic interventions are rarely (if ever) achievable in the treatment of stroke and trauma patients. Conversely, interventions that block the post-mitochondrial phase of apoptosis (if administered within the first few hours after the accident) hold great promises for the development of novel neuroprotective strategies. In animal models of acute neuronal injury, the inhibition of caspases, apoptosis-inducing factor (AIF) and other apoptotic effectors can confer significant neuroprotection. Our review recapitulates the results of these studies and proposes novel strategies of inhibiting post-mitochondrial apoptosis in neurons. [Copyright &y& Elsevier]

Abstract: Light emission from the bacterial luciferase operon has been variously exploited during last two decades. The use of convenient inducible promoters has granted significant degrees of specificity to whole cell-based assays for high-throughput screening and environmental monitoring. Nevertheless, unexplained unspecific responses have been repeatedly reported. Here, we show that the impairment of the intracellular biochemical equilibrium interferes with the luminescence produced by Escherichia coli and Staphylococcus aureus strains carrying the lux operon under constitutive or inducible control. Compounds as trimethoprim and methotrexate, by indirectly inducing NADPH accumulation, enhance light emission. Conversely, molecules driving the cell toward an oxidized state, as dimethyl sulfoxide, inhibit luminescence. These findings fit into the accepted biochemical pathway for bioluminescence, where NADPH and reducing equivalents are necessary for the production of luciferase substrates, although they do not directly take part into the light-emitting reaction. Moreover, we investigated the influence of induction timing upon the bioluminescence response from inducible reporter systems and demonstrated a correlation between the emitted light and the growth phase at which induction is performed. Our results provide explanations for some unspecific responses recorded so far in whole cell-based luminescent biosensors and emphasize the intrinsic limitations of this kind of reporting system. [Copyright &y& Elsevier]

Recent findings demonstrate that transient genetic inhibition of autophagy promotes age-associated pathologies in mice. While autophagy restoration effectively counteracts such disorders, it also exacerbates the incidence of various solid and hematological tumors. These data may cast additional shadows on the clinical potential of autophagy inhibition for cancer therapy. [ABSTRACT FROM AUTHOR]

Calreticulin (CALR) exposure on the cell surface is known to deliver robust pro-phagocytic signals to myeloid cells. In Nature , Sen Santara et al. demonstrate that surface-exposed CALR also operates as an endogenous activator of natural killer (NK) cells. Collectively, these findings suggest that CALR exposure orchestrates multiple facets of innate immunosurveillance. [ABSTRACT FROM AUTHOR]

Tumor progression and resistance to treatment are often accompanied by the polarization of malignant cells towards a mesenchymal or poorly differentiated state. Such a transition generates an accrued vulnerability to the induction of ferroptosis, potentially paving the way to novel therapeutic strategies for targeting residual disease in patients with cancer. [ABSTRACT FROM AUTHOR]

Recent findings from a prospective clinical study involving multiregion whole-exome sequencing suggest that driver mutations in cancer-relevant genes including EGFR and TP53 are often clonal and precede whole-genome duplication events in early lung carcinogenesis. This paves an expressway to extensive subclonal diversification, elevated intratumoral heterogeneity, and dismal disease outcome. [ABSTRACT FROM AUTHOR]

At odds with its nuclear counterpart, extranuclear promyelocytic leukemia constitutively inhibits autophagy, hence limiting cancer progression. These data raise the interesting possibility that some tumor suppressors have become specialized to operate at multiple subcellular compartments for counteracting different aspects of the oncogenic process. [ABSTRACT FROM AUTHOR]

Autophagy is quintessential for the maintenance of cellular homeostasis in all eukaryotic cells, explaining why both normal and malignant cells benefit from proficient autophagic responses. Moreover, autophagy is intimately involved in the immunological control of malignant transformation, tumor progression and response to therapy. However, the net effect of autophagy activation or inhibition on the natural growth or therapeutic response of tumors evolving in immunocompetent hosts exhibits a considerable degree of context dependency. Here, we discuss the complex cross-talk between autophagy and immuno-oncology as delineated by genetic and pharmacological approaches in mouse models of cancer. Unlabelled Image [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are known for their superior tumor-initiating and tumor-repopulating potential, partly reflecting their pronounced ability to evade immune recognition. Liu and colleagues recently identified a new aldehyde dehydrogenase (ALDH)-dependent mechanism whereby triple-negative breast CSCs evade immunosurveillance upon recruitment of myeloid-derived suppressor cells. [ABSTRACT FROM AUTHOR]

Two recent reports in Nature highlight a novel mechanism of immunoevasion that relies on the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-dependent epigenetic suppression of endogenous retroelements in melanoma cells. Because SETDB1 is highly expressed by the stem cell compartment, these findings delineate an innovative strategy for restoring cancer stem cell immunosurveillance. [ABSTRACT FROM AUTHOR]

Two recent reports in Nature highlight a novel mechanism of immunoevasion that relies on the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-dependent epigenetic suppression of endogenous retroelements in melanoma cells. Because SETDB1 is highly expressed by the stem cell compartment, these findings delineate an innovative strategy for restoring cancer stem cell immunosurveillance. [ABSTRACT FROM AUTHOR]

Immunotherapy is radically changing the clinical management of patients affected by an increasingly wide array of tumours. However, not all patients achieve long-term clinical benefits from immunotherapy as a standalone treatment, calling for the development of regimens that combine various interventions. Radiotherapy stands out as a particularly promising candidate in this setting, not only because of its established safety profile, but also because radiotherapy has the potential ability to mediate robust immunostimulatory effects that could synergise with immunotherapy in systemic tumour control. However, optimal radioimmunotherapy regimens might call for the redefinition of conventional radiotherapy doses and fractionation schedules. In this Series paper, we discuss current approaches to improve the efficacy and reduce the toxicity of radioimmunotherapy for the management of cancer. [ABSTRACT FROM AUTHOR]

Cytomegalovirus infection is associated with cytoskeletal alterations and cell swelling (cytomegaly), which have been attributed to the viral mitochondria-localized inhibitor of apoptosis (vMIA) protein. In a recent issue of Science, showed that the antiviral host protein viperin is co-opted to function with vMIA for facilitating infection. [Copyright &y& Elsevier]

Mitochondria control various processes that are integral to cellular and organismal homeostasis, including Ca2+ fluxes, bioenergetic metabolism, and cell death. Perhaps not surprisingly, multiple pathogenic bacteria have evolved strategies to subvert mitochondrial functions in support of their survival and dissemination. Here, we discuss nonimmunological pathogenic mechanisms that converge on the ability of bacteria to control the mitochondrial compartment of host cells. Mitochondria, the evolutionary successors of an ancient endosymbiotic prokaryote, occupy a central position in the biology of modern eukaryotic cells. Numerous pathogenic bacteria have evolved strategies to subvert the mitochondrial functions of host cells in support of proliferation and dissemination. The control of metabolism, Ca2+ fluxes, autophagy, and regulated cell death at mitochondrial level provides invading pathogens with a considerable evolutionary advantage. [ABSTRACT FROM AUTHOR]

Tumors are not immunologically silent but evolve and respond to therapy in the context of a continuous, bi-directional interaction with the host immune system. In line with this notion, several clinically successful chemotherapeutics have been shown to mediate antineoplastic effects as they (re)activate an anticancer immune response that is generally executed by lymphoid cells. Myeloid cells play a central role in this process, not only because they critically regulate the activity of T and B lymphocytes, but also because they exert direct tumoricidal effects, at least in some settings. Here, we discuss the impact of various myeloid cell populations, including macrophages, dendritic cells and myeloid-derived suppressor cells, on the efficacy of anticancer chemotherapy. [ABSTRACT FROM AUTHOR]

Recent findings (Tsabar et al.) demonstrate that human cancer cells that evade the cell cycle blockage normally imposed by DNA damage experience sustained p53 signaling upon MDM2 degradation by caspase 2. Such a response may be connected to the delivery of immunostimulatory signals to ensure the elimination of genetically instable cancer cells. [ABSTRACT FROM AUTHOR]

Abstract: Erlotinib and gefitinib, two inhibitors of the epidermal growth factor receptor (EGFR), can stimulate apoptosis and differentiation of myeloid cell lines that lack EGFR, unveiling a novel, therapeutically exploitable off-target effect of tyrosine kinase inhibitors. Here, we performed a side-by-side comparison of erlotinib and gefitinib effects on a broad spectrum of malignant myeloid cell lines, as well as on primary myeloblasts freshly purified from the bone marrow of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Both erlotinib and gefitinib induce apoptosis of a cell line (KG-1) that represents AML, and differentiation in another cell line (P39) derived from a patient with high-risk MDS. In this setting, erlotinib was more efficient than gefitinib. Erlotinib and gefitinib were equipotent in inducing apoptosis of primary CD34+ myeloblasts from MDS and AML patients, yet had no toxic effect on CD34+ progenitor cells from healthy donors. Although the response of individual MDS and AML patients in vitro was highly heterogeneous, the pro-apoptotic effects of erlotinib and gefitinib correlated significantly. These results suggest that erlotinib and gefitinib share a mechanistically related off-target effect that may be taken advantage of for the therapy of MDS and AML. [Copyright &y& Elsevier]

At odds with conventional chemotherapeutics, targeted anticancer agents are designed to inhibit precise molecular alterations that support oncogenesis or tumor progression. Despite such an elevated degree of molecular specificity, many clinically employed and experimental targeted anticancer agents also mediate immunostimulatory or immunosuppressive effects that (at least in some settings) influence therapeutic efficacy. Here, we discuss the main immunomodulatory effects of targeted anticancer agents and explore potential avenues to harness them in support of superior clinical efficacy. [ABSTRACT FROM AUTHOR]

Bcl-2 proteins are widely known as key controllers of mitochondrial outer membrane permeabilization, arguably the most important step of intrinsic apoptosis. Accumulating evidence indicate that most, if not all, members of the Bcl-2 protein family also mediate a number of apoptosis-unrelated functions. Intriguingly, many of these functions ultimately impinge on cell fate decisions via apoptosis-dependent or -independent mechanisms, delineating a complex network through which Bcl-2 family members regulate cell survival and death. Here, we critically discuss the mechanisms through which Bcl-2 proteins influence cell fate as they regulate autophagy, cellular senescence, inflammation, bioenergetic metabolism, Ca2+ fluxes, and redox homeostasis. The Bcl-2 protein family is widely known for controlling mitochondrial outer membrane permeabilization (MOMP), a key step in apoptotic cell death. Most, if not all, Bcl-2 family members have been shown to influence cellular processes apparently unrelated to apoptosis. Regulation of autophagy, cellular senescence, inflammation, bioenergetic metabolism, Ca2+ fluxes, and redox homeostasis by Bcl-2 proteins ultimately impacts on cell fate. Modulating the Bcl-2 protein family holds promise as a potential therapeutic approach for numerous diseases beyond cancer. [ABSTRACT FROM AUTHOR]

In most (if not all) solid tumors, malignant cells are outnumbered by their non-malignant counterparts, including immune, endothelial and stromal cells. However, while the mechanisms whereby cancer cells adapt to microenvironmental perturbations have been studied in great detail, relatively little is known on stress responses in non-malignant compartments of the tumor microenvironment. Here, we discuss the mechanisms whereby cancer-associated fibroblasts and other cellular components of the tumor stroma react to stress in the context of an intimate crosstalk with malignant, endothelial and immune cells, and how such crosstalk influences disease progression and response to treatment. [ABSTRACT FROM AUTHOR]

Evolving neoplasms accumulate non-synonymous mutations at a high rate, potentially enabling the expression of antigenic epitopes that can be recognized by the immune system. Since they are not covered by central tolerance, such tumor neoantigens (TNAs) should be under robust immune control as they surge. However, genetic defects that impair cancer cell eradication by the immune system coupled with the establishment of local immunosuppression can enable TNA accumulation, which is generally associated with improved clinical sensitivity to various immunotherapies. Here, we explore how tumor-intrinsic factors and immunological processes shape the mutational and antigenic landscape of evolving neoplasms to influence clinical responses to immunotherapy, and propose strategies to achieve robust immunological control of the disease despite disabled immunosurveillance. Highlights The recognition of TNAs by the host immune system has a key role in natural immunosurveillance and dictates the outcome of most (if not all) current cancer (immuno)therapies. A panel of tumor-intrinsic and microenvironmental factors influence TNA evolution over space and time, partially explaining the heterogeneity of clinical responses to (immuno)therapies. The tumor and its host coevolve in a highly dynamic manner, which shapes the mechanisms whereby progressing neoplasms evade immune recognition as they become resistant to (immuno)therapy. Unveiling the trajectories of TNA evolution may help define quantitative, qualitative, and temporal aspects of the anticancer immune response that can assist clinical decision-making. [ABSTRACT FROM AUTHOR]

Besides constituting a first layer of defense against microbial challenges, the detection of cytosolic DNA is fundamental for mammalian organisms to control malignant transformation and tumor progression. The accumulation of DNA in the cytoplasm can initiate the proliferative inactivation (via cellular senescence) or elimination (via regulated cell death) of neoplastic cell precursors. Moreover, cytosolic DNA sensing is intimately connected to the secretion of cytokines that support innate and adaptive antitumor immunity. Here, we discuss the molecular mechanisms whereby cytosolic DNA enables cell-intrinsic and -extrinsic oncosuppression, and their relevance for the development of novel therapeutic approaches that reinstate anticancer immunosurveillance. Besides constituting a first layer of defense against microbial challenges, the detection of cytosolic DNA is fundamental for mammalian organisms to control malignant transformation and tumor progression. The accumulation of DNA in the cytoplasm can initiate the proliferative inactivation (via cellular senescence) or elimination (via regulated cell death) of neoplastic cell precursors. Moreover, cytosolic DNA sensing is intimately connected to the secretion of cytokines that support innate and adaptive antitumor immunity. Here, we discuss the molecular mechanisms whereby cytosolic DNA enables cell-intrinsic and -extrinsic oncosuppression, and their relevance for the development of novel therapeutic approaches that reinstate anticancer immunosurveillance. [ABSTRACT FROM AUTHOR]

The geomorphology of the Italian territory causes the incidence of many disasters like earthquakes and floods, with the consequent production of large volumes of waste. The management of such huge flows, produced in a very short time, may have a high impact on the whole emergency response. Moreover, historical data related to disaster waste management are often not easily accessible; on the other hand, the availability of data concerning previous events could support the emergency managers, that have to take a decision in a very short time. In this context, the present paper analyses four relevant recent case studies in Italy, dealing with disaster waste management after geologic and hydrologic natural events. Significant differences have been observed in the quantity and types of generated wastes, and, also, in the management approach. Such differences are mainly associated with the kind of disaster (i.e. earthquake vs. flood), to the geographical location (i.e. internal vs. coastal area), to the urbanisation level (i.e. industrial vs. urban). The study allowed the identification of both strengths and weaknesses of the applied waste management strategies, that represent “lessons to learn” for future scenarios. Even though it deals with Italian case studies, this manuscript may have a high impact also at international level, making available for the first-time emergency waste management data, that are considered an indispensable support for decision makers. [ABSTRACT FROM AUTHOR]

The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell-intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells. [ABSTRACT FROM AUTHOR]

Several insults cause the inner mitochondrial membrane to abruptly lose osmotic homeostasis, hence initiating a regulated variant of cell death known as ‘mitochondrial permeability transition’ (MPT)-driven necrosis. MPT provides an etiological contribution to several human disorders characterized by the acute loss of post-mitotic cells, including cardiac and cerebral ischemia. Nevertheless, the precise molecular determinants of MPT remain elusive, which considerably hampers the development of clinically implementable cardio- or neuroprotective strategies targeting this process. We summarize recent findings shedding new light on the supramolecular entity that mediates MPT, the so-called ‘permeability transition pore complex’ (PTPC). Moreover, we discuss hitherto unresolved controversies on MPT and analyze the major obstacles that still preclude the complete understanding and therapeutic targeting of this process. [ABSTRACT FROM AUTHOR]

Abstract: Preclinical and clinical findings suggest that tumor-specific immune responses may be responsible – at least in part – for the clinical success of therapeutic regimens that rely on immunogenic cell death (ICD) inducers, including anthracyclines and oxaliplatin. The molecular pathways whereby some, but not all, cytotoxic agents promote bona fide ICD remain to be fully elucidated. Nevertheless, a central role for the endoplasmic reticulum (ER) stress response has been revealed in all scenarios of ICD described thus far. Hence, components of the ER stress machinery may constitute clinically relevant druggable targets for the induction of ICD. In this review, we will summarize recent findings in the field of ICD research with a special focus on ER stress mechanisms and their implication for cancer therapy. [Copyright &y& Elsevier]