Autophagy and autophagy-related pathways in cancer.

Maintenance of protein homeostasis and organelle integrity and function is critical for cellular homeostasis and cell viability. Autophagy is the principal mechanism that mediates the delivery of various cellular cargoes to lysosomes for degradation and recycling. A myriad of studies demonstrate important protective roles for autophagy against disease. However, in cancer, seemingly opposing roles of autophagy are observed in the prevention of early tumour development versus the maintenance and metabolic adaptation of established and metastasizing tumours. Recent studies have addressed not only the tumour cell intrinsic functions of autophagy, but also the roles of autophagy in the tumour microenvironment and associated immune cells. In addition, various autophagy-related pathways have been described, which are distinct from classical autophagy, that utilize parts of the autophagic machinery and can potentially contribute to malignant disease. Growing evidence on how autophagy and related processes affect cancer development and progression has helped guide efforts to design anticancer treatments based on inhibition or promotion of autophagy. In this Review, we discuss and dissect these different functions of autophagy and autophagy-related processes during tumour development, maintenance and progression. We outline recent findings regarding the role of these processes in both the tumour cells and the tumour microenvironment and describe advances in therapy aimed at autophagy processes in cancer.

mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux.

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm. This process requires DRAM-1, which binds the membrane carrier protein SCAMP3 and the amino acid transporters SLC1A5 and LAT1, directing them to lysosomes and permitting efficient mTORC1 activation. Consequently, we show that loss of DRAM-1 also impacts pathways regulated by mTORC1, including insulin signaling, glycemic balance, and adipocyte differentiation. Interestingly, although DRAM-1 can promote autophagy, this effect on mTORC1 is autophagy independent, and autophagy only becomes important for mTORC1 activation when DRAM-1 is deleted. These findings provide important insights into mTORC1 activation and highlight the importance of DRAM-1 in growth control, metabolic homeostasis, and differentiation.

Autophagy in major human diseases.

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.

Emerging Chalcohalide Materials for Energy Applications.

Semiconductors with multiple anions currently provide a new materials platform from which improved functionality emerges, posing new challenges and opportunities in material science. This review has endeavored to emphasize the versatility of the emerging family of semiconductors consisting of mixed chalcogen and halogen anions, known as "chalcohalides". As they are multifunctional, these materials are of general interest to the wider research community, ranging from theoretical/computational scientists to experimental materials scientists. This review provides a comprehensive overview of the development of emerging Bi- and Sb-based as well as a new Cu, Sn, Pb, Ag, and hybrid organic-inorganic perovskite-based chalcohalides. We first highlight the high-throughput computational techniques to design and develop these chalcohalide materials. We then proceed to discuss their optoelectronic properties, band structures, stability, and structural chemistry employing theoretical and experimental underpinning toward high-performance devices. Next, we present an overview of recent advancements in the synthesis and their wide range of applications in energy conversion and storage devices. Finally, we conclude the review by outlining the impediments and important aspects in this field as well as offering perspectives on future research directions to further promote the development of chalcohalide materials in practical applications in the future.

Bromodomain Protein BRD4 Is a Transcriptional Repressor of Autophagy and Lysosomal Function.

Autophagy is a membrane-trafficking process that directs degradation of cytoplasmic material in lysosomes. The process promotes cellular fidelity, and while the core machinery of autophagy is known, the mechanisms that promote and sustain autophagy are less well defined. Here we report that the epigenetic reader BRD4 and the methyltransferase G9a repress a TFEB/TFE3/MITF-independent transcriptional program that promotes autophagy and lysosome biogenesis. We show that BRD4 knockdown induces autophagy in vitro and in vivo in response to some, but not all, situations. In the case of starvation, a signaling cascade involving AMPK and histone deacetylase SIRT1 displaces chromatin-bound BRD4, instigating autophagy gene activation and cell survival. Importantly, this program is directed independently and also reciprocally to the growth-promoting properties of BRD4 and is potently repressed by BRD4-NUT, a driver of NUT midline carcinoma. These findings therefore identify a distinct and selective mechanism of autophagy regulation.

ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis.

The role of autophagy in cancer is complex. Both tumor-promoting and tumor-suppressive effects are reported, with tumor type, stage and specific genetic lesions dictating the role. This calls for analysis in models that best recapitulate each tumor type, from initiation to metastatic disease, to specifically understand the contribution of autophagy in each context. Here, we report the effects of deleting the essential autophagy gene Atg7 in a model of pancreatic ductal adenocarcinoma (PDAC), in which mutant KrasG12D and mutant Trp53172H are induced in adult tissue leading to metastatic PDAC. This revealed that Atg7 loss in the presence of KrasG12D/+ and Trp53172H/+ was tumor promoting, similar to previous observations in tumors driven by embryonic KrasG12D/+ and deletion of Trp53. However, Atg7 hemizygosity also enhanced tumor initiation and progression, even though this did not ablate autophagy. Moreover, despite this enhanced progression, fewer Atg7 hemizygous mice had metastases compared with animals wild type for this allele, indicating that ATG7 is a promoter of metastasis. We show, in addition, that Atg7+/- tumors have comparatively lower levels of succinate, and that cells derived from Atg7+/- tumors are also less invasive than those from Atg7+/+ tumors. This effect on invasion can be rescued by ectopic expression of Atg7 in Atg7+/- cells, without affecting the autophagic capacity of the cells, or by treatment with a cell-permeable analog of succinate. These findings therefore show that ATG7 has roles in invasion and metastasis that are not related to the role of the protein in the regulation of autophagy.

Glycan degradation promotes macroautophagy.

Macroautophagy promotes cellular homeostasis by delivering cytoplasmic constituents to lysosomes for degradation [Mizushima, Nat. Cell Biol. 20, 521-527 (2018)]. However, while most studies have focused on the mechanisms of protein degradation during this process, we report here that macroautophagy also depends on glycan degradation via the glycosidase, α-l-fucosidase 1 (FUCA1), which removes fucose from glycans. We show that cells lacking FUCA1 accumulate lysosomal glycans, which is associated with impaired autophagic flux. Moreover, in a mouse model of fucosidosis-a disease characterized by inactivating mutations in FUCA1 [Stepien et al., Genes (Basel) 11, E1383 (2020)]-glycan and autophagosome/autolysosome accumulation accompanies tissue destruction. Mechanistically, using lectin capture and mass spectrometry, we identified several lysosomal enzymes with altered fucosylation in FUCA1-null cells. Moreover, we show that the activity of some of these enzymes in the absence of FUCA1 can no longer be induced upon autophagy stimulation, causing retardation of autophagic flux, which involves impaired autophagosome-lysosome fusion. These findings therefore show that dysregulated glycan degradation leads to defective autophagy, which is likely a contributing factor in the etiology of fucosidosis.

Resolving Multielement Semiconductor Nanocrystals at the Atomic Level: Complete Deciphering of Domains and Order in Complex CuαZnßSnγSeδ (CZTSe) Tetrapods.

Semiconductor nanocrystals (NCs) with high elemental and structural complexity can be engineered to tailor for electronic, photovoltaic, thermoelectric, and battery applications etc. However, this greater complexity causes ambiguity in the atomic structure understanding. This in turn hinders the mechanistic studies of nucleation and growth, the theoretical calculations of functional properties, and the capability to extend functional design across complementary semiconductor nanocrystals. Herein, we successfully deciphered the atomic arrangements of 4 different nanocrystal domains in CuαZnßSnγSeδ (CZTSe) nanocrystals using crucial zone axis analysis on multiple crystals in different orientations. The results show that the essence of crystallographic progression from binary to multielemental semiconductors is actually the change of theoretical periodicity. This transition is caused by decreased symmetry in the crystal instead of previously assumed crystal deformation. We further reveal that these highly complex crystalline entities have highly ordered element arrangements as opposed to the previous understanding that their elemental orderings are random.

Mannose impairs tumour growth and enhances chemotherapy.

It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.

50 years on and still very much alive: 'Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics'.

Cell death is part of the lifecycle of every multicellular organism. Nineteenth-century pathologists already recognised that organised forms of cell death must exist to explain the demise and turnover of cells during metamorphosis (of insects), embryogenesis and normal tissue homoeostasis [1]. Nevertheless, Kerr, Wyllie and Currie in their seminal paper of 1972, were the first to collate and define the distinct morphological features of controlled cell death in different contexts [2]. To describe the processes of cell deletion observed under both physiological and pathological conditions, they coined the term 'Apoptosis' (derived from the Greek word 'ἀπόπτωσις', meaning 'dropping off or falling off' of petals from flowers). Kerr, Wyllie and Currie defined apoptosis as a mechanism 'complementary to mitosis in the regulation of animal cell populations'. In addition, they already recognised the potential to use this programmed form of cell death for cancer therapy, but they also emphasised the occurrence of apoptosis during cancer development. In this article, some 50 years after its initial publication in The British Journal of Cancer, we revaluate and put the authors initial assumptions and general concepts about apoptosis into the context of modern-day biology.

Cu Current Collector with Binder-Free Lithiophilic Nanowire Coating for High Energy Density Lithium Metal Batteries.

Despite significant efforts to fabricate high energy density (ED) lithium (Li) metal anodes, problems such as dendrite formation and the need for excess Li (leading to low N/P ratios) have hampered Li metal battery (LMB) development. Here, the use of germanium (Ge) nanowires (NWs) directly grown on copper (Cu) substrates (Cu-Ge) to induce lithiophilicity and subsequently guide Li ions for uniform Li metal deposition/stripping during electrochemical cycling is reported. The NW morphology along with the formation of the Li15 Ge4 phase promotes uniform Li-ion flux and fast charge kinetic, resulting in the Cu-Ge substrate demonstrating low nucleation overpotentials of 10 mV (four times lower than planar Cu) and high Columbic efficiency (CE) efficiency during Li plating/stripping. Within a full-cell configuration, the Cu-Ge@Li - NMC cell delivered a 63.6% weight reduction at the anode level compared to a standard graphite-based anode, with impressive capacity retention and average CE of over 86.5% and 99.2% respectively. The Cu-Ge anodes are also paired with high specific capacity sulfur (S) cathodes, further demonstrating the benefits of developing surface-modified lithiophilic Cu current collectors, which can easily be integrated at the industrial scale.

Lithiophilic Nanowire Guided Li Deposition in Li Metal Batteries.

Lithium (Li) metal batteries (LMBs) provide superior energy densities far beyond current Li-ion batteries (LIBs) but practical applications are hindered by uncontrolled dendrite formation and the build-up of dead Li in "hostless" Li metal anodes. To circumvent these issues, we created a 3D framework of a carbon paper (CP) substrate decorated with lithiophilic nanowires (silicon (Si), germanium (Ge), and SiGe alloy NWs) that provides a robust host for efficient stripping/plating of Li metal. The lithiophilic Li22 Si5 , Li22 (Si0.5 Ge0.5 )5, and Li22 Ge5 formed during rapid Li melt infiltration prevented the formation of dead Li and dendrites. Li22 Ge5 /Li covered CP hosts delivered the best performance, with the lowest overpotentials of 40 mV (three times lower than pristine Li) when cycled at 1 mA cm-2 /1 mAh cm-2 for 1000 h and at 3 mA cm-2 /3 mAh cm-2 for 500 h. Ex situ analysis confirmed the ability of the lithiophilic Li22 Ge5 decorated samples to facilitate uniform Li deposition. When paired with sulfur, LiFePO4, and NMC811 cathodes, the CP-LiGe/Li anodes delivered 200 cycles with 82%, 93%, and 90% capacity retention, respectively. The discovery of the highly stable, lithiophilic NW decorated CP hosts is a promising route toward stable cycling LMBs and provides a new design motif for hosted Li metal anodes.

Multipod Bi(Cu2-xS)n Nanocrystals formed by Dynamic Cation-Ligand Complexation and Their Use as Anodes for Potassium-Ion Batteries.

We report the formation of an intermediate lamellar Cu-thiolate complex, and tuning its relative stability using alkylphosphonic acids are crucial to enabling controlled heteronucleation to form Bi(Cu2-xS)n heterostructures with a tunable number of Cu2-xS stems on a Bi core. The denticity of the phosphonic acid group, concentration, and chain length of alkylphosphonic acids are critical factors determining the stability of the Cu-thiolate complex. Increasing the stability of the Cu-thiolate results in single Cu2-xS stem formation, and decreased stability of the Cu-thiolate complex increases the degree of heteronucleation to form multiple Cu2-xS stems on the Bi core. Spatially separated multiple Cu2-xS stems transform into a support network to hold a fragmented Bi core when used as an anode in a K-ion battery, leading to a more stable cycling performance showing a specific capacity of ∼170 mAh·g-1 after 200 cycles compared to ∼111 mAh·g-1 for Bi-Cu2-xS single-stem heterostructures.

Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis.

During apoptosis, pro-apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP Such caspase-independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS-STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS-STING signalling pathway. Using super-resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP In a temporal manner, we find that following MOMP, BAX/BAK-mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK-dependent MOMP Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase-independent cell death.

Phosphine free synthesis of copper telluride nanocrystals in 1D and 2D shapes using Dipehylditelluride (DPDTe) as an air-stable source.

In this paper, we have developed a 'phosphine-free' method for synthesising copper telluride nanocrystals using diphenyl ditelluride as an air-stable tellurium source. The diphenyl ditelluride is shown to have optimal reactivity for the colloidal synthesis of Cu2Te, allowing optimal control over the phase and morphology. Using this unexplored Te precursor for copper telluride synthesis, 1D nanorods of hexagonal phase (Cu2Te) were synthesised at a moderate temperature of 180 °C. The precise control over key parameters for this system results in Cu2-xTe nanocrystals forming with varied shapes (1D nanorods and 2D nanoplates), sizes, and crystal phases (hexagonal Cu2Te and orthorhombic Cu1.43Te).

Molecular definitions of autophagy and related processes.

Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research.

A Nanowire Nest Structure Comprising Copper Silicide and Silicon Nanowires for Lithium-Ion Battery Anodes with High Areal Loading.

High loading (>1.6 mg cm-2 ) of Si nanowires (NWs) is achieved by seeding the growth from a dense array of Cu15 Si4 NWs using tin seeds. A one-pot synthetic approach involves the direct growth of CuSi NWs on Cu foil that acts as a textured surface for Sn adhesion and Si NW nucleation. The high achievable Si NW loading is enabled by the high surface area of CuSi NWs and bolstered by secondary growth of Si NWs as branches from both Si and CuSi NW stems, forming a dense Si active layer, interconnected with an electrically conducting CuSi array (denoted Si/CuSi). When employed as Li-ion battery anodes, the Si/CuSi nest structure demonstrates impressive rate performance, reaching 4.1 mAh cm-2 at C/20, 3.1 mAh cm-2 at C/5, and 0.8 mAh cm-2 at 6C. Also, Si/CuSi shows remarkable long-term stability, delivering a stable areal capacity of 2.2 mAh cm-2 after 300 cycles. Overall, complete anode fabrication is achieved within a single reaction by employing an inexpensive Sn powder approach.

Direct Growth of Si, Ge, and Si-Ge Heterostructure Nanowires Using Electroplated Zn: An Inexpensive Seeding Technique for Li-Ion Alloying Anodes.

A scalable and cost-effective process is used to electroplate metallic Zn seeds on stainless steel substrates. Si and Ge nanowires (NWs) are subsequently grown by placing the electroplated substrates in the solution phase of a refluxing organic solvent at temperatures >430 °C and injecting the respective liquid precursors. The native oxide layer formed on reactive metals such as Zn can obstruct NW growth and is removed in situ by injecting the reducing agent LiBH4 . The findings show that the use of Zn as a catalyst produces defect-rich Si NWs that can be extended to the synthesis of Si-Ge axial heterostructure NWs with an atomically abrupt Si-Ge interface. As an anode material, the as grown Zn seeded Si NWs yield an initial discharge capacity of 1772 mAh g-1 and a high capacity retention of 85% after 100 cycles with the active participation of both Si and Zn during cycling. Notably, the Zn seeds actively participate in the Li-cycling activities by incorporating into the Si NWs body via a Li-assisted welding process, resulting in restructuring the NWs into a highly porous network structure that maintains a stable cycling performance.

P2S5 Reactive Flux Method for the Rapid Synthesis of Mono- and Bimetallic 2D Thiophosphates M2-xM'xP2S6.

We report a reactive flux technique using the common reagent P2S5 and metal precursors developed to circumvent the synthetic bottleneck for producing high-quality single- and mixed-metal two-dimensional (2D) thiophosphate materials. For the monometallic compound, M2P2S6 (M = Ni, Fe, and Mn), phase-pure materials were quickly synthesized and annealed at 650 °C for 1 h. Crystals of dimensions of several millimeters were grown for some of the metal thiophosphates using optimized heating profiles. The homogeneity of the bimetallic thiophosphates MM'P2S6 (M, M' = Ni, Fe, and Mn) was elucidated using energy-dispersive X-ray spectroscopy and Rietveld refinement. The quality of the selected materials was characterized by transmission electron microscopy and atomic force microscopy measurements. We report two novel bimetallic thiophosphates, MnCoP2S6 and FeCoP2S6. The Ni2P2S6 and MnNiP2S6 flux reactions were monitored in situ using variable-temperature powder X-ray diffraction to understand the formation reaction pathways. The phases were directly formed in a single step at approximately 375 °C. The work functions of the semiconducting materials were determined and ranged from 5.28 to 5.72 eV.

Extracellular adenosine sensing-a metabolic cell death priming mechanism downstream of p53.

Tumor cells undergo changes in metabolism to meet their energetic and anabolic needs. It is conceivable that mechanisms exist to sense these changes and link them to pathways that eradicate cells primed for cancer development. We report that the tumor suppressor p53 activates a cell death priming mechanism that senses extracellular adenosine. Adenosine, the backbone of ATP, accumulates under conditions of cellular stress or altered metabolism. We show that its receptor, A2B, is upregulated by p53. A2B expression has little effect on cell viability, but ligand engagement activates a caspase- and Puma-dependent apoptotic response involving downregulation of antiapoptotic Bcl-2 proteins. Stimulation of A2B also significantly enhances cell death mediated by p53 and upon accumulation of endogenous adenosine following chemotherapeutic drug treatment and exposure to hypoxia. Since extracellular adenosine also accumulates within many solid tumors, this distinct p53 function links programmed cell death to both a cancer- and therapy-associated metabolic change.