The epithelial–mesenchymal transition (EMT) program has emerged as a central driver of tumor malignancy. Moreover, the recently uncovered link between passage through an EMT and acquisition of stem-like properties indicates that activation of the EMT programs serves as a major mechanism for generating cancer stem cells (CSCs); that is, a subpopulation of cancer cells that are responsible for initiating and propagating the disease. In this review, we summarize the evidence supporting the widespread involvement of the EMT program in tumor pathogenesis and attempt to rationalize the connection between the EMT program and acquisition of stem cell traits. We propose that epithelial–mesenchymal plasticity is likely controlled by multiple varients of the core EMT program, and foresee the need to resolve the various programs and the molecular mechanisms that underlie them.
DNA double-strand breaks (DSBs) are cytotoxic lesions that threaten genomic integrity. Failure to repair a DSB has deleterious consequences, including genomic instability and cell death. Indeed, misrepair of DSBs can lead to inappropriate end-joining events, which commonly underlie oncogenic transformation due to chromosomal translocations. Typically, cells employ two main mechanisms to repair DSBs: homologous recombination (HR) and classical nonhomologous end joining (C-NHEJ). In addition, alternative error-prone DSB repair pathways, namely alternative end joining (alt-EJ) and single-strand annealing (SSA), have been recently shown to operate in many different conditions and to contribute to genome rearrangements and oncogenic transformation. Here, we review the mechanisms regulating DSB repair pathway choice, together with the potential interconnections between HR and the annealing-dependent error-prone DSB repair pathways.
Highlights • The characteristics and mechanisms of ectosomes and exosomes are defined. • Exosomes are released on the exocytosis of MVBs, whereas ectosomes are assembled and released from the plasma membrane. • Interactions of vesicles with target cells and vesicle navigation are illustrated. • The role of vesicles in cancer diagnosis and therapy is discussed.
Stress granules are assemblies of untranslating messenger ribonucleoproteins (mRNPs) that form from mRNAs stalled in translation initiation. Stress granules form through interactions between mRNA-binding proteins that link together populations of mRNPs. Interactions promoting stress granule formation include conventional protein–protein interactions as well as interactions involving intrinsically disordered regions (IDRs) of proteins. Assembly and disassembly of stress granules are modulated by various post-translational modifications as well as numerous ATP-dependent RNP or protein remodeling complexes, illustrating that stress granules represent an active liquid wherein energy input maintains their dynamic state. Stress granule formation modulates the stress response, viral infection, and signaling pathways. Persistent or aberrant stress granule formation contributes to neurodegenerative disease and some cancers.
Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid -based reactive oxygen species (ROS), particularly lipid hydroperoxides. This form of iron -dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.
Highlights • NAD+ plays a key role in regulating metabolism and circadian rhythm through sirtuins. • NAD+ becomes limiting during aging, affecting sirtuins’ activities. • NAD+ decline is likely to be due to a NAD+ biosynthesis defect and increased depletion. • Supplementing key NAD+ intermediates can restore NAD+ levels and ameliorate age-associated pathophysiologies.
AMP-activated protein kinase (AMPK) is a key regulator of energy balance expressed ubiquitously in eukaryotic cells. Here we review the canonical adenine nucleotide-dependent mechanism that activates AMPK when cellular energy status is compromised, as well as other, noncanonical activation mechanisms. Once activated, AMPK acts to restore energy homeostasis by promoting catabolic pathways, resulting in ATP generation, and inhibiting anabolic pathways that consume ATP. We also review the various hypothesis-driven and unbiased approaches that have been used to identify AMPK substrates and have revealed substrates involved in both metabolic and non-metabolic processes. We particularly focus on methods for identifying the AMPK target recognition motif and how it can be used to predict new substrates.
Highlights • The circadian clock generates molecular rhythms with 24 h periodicity. • Circadian control of physiology is distributed to peripheral tissues. • 24 h timing arises from the ordered recruitment of clock proteins to promoters. • Many mechanisms are used to generate rhythmic output from the core molecular clock. • Clocks integrate with systemic cues to give flexibility to circadian physiology.
Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound carriers with complex cargoes including proteins, lipids, and nucleic acids. While the release of EVs was previously thought to be only a mechanism to discard nonfunctional cellular components, increasing evidence implicates EVs as key players in intercellular and even interorganismal communication. EVs confer stability and can direct their cargoes to specific cell types. EV cargoes also appear to act in a combinatorial manner to communicate directives to other cells. This review focuses on recent findings and knowledge gaps in the area of EV biogenesis, release, and uptake. In addition, we highlight examples whereby EV cargoes control basic cellular functions, including motility and polarization, immune responses, and development, and contribute to diseases such as cancer and neurodegeneration.
Highlights • Cellular amino acid levels tightly control the activity of the master growth regulator mTORC1. • The emergence of molecular details on how the mTORC1 pathway senses amino acids is an important advance in the field. • The amino acid sensing pathway is composed of several multicomponent complexes that act in concert to convey changes in amino acid levels to mTORC1.
Selective autophagy regulates the abundance of specific cellular components via a specialized arsenal of factors, termed autophagy receptors, that target protein complexes, aggregates, and whole organelles into lysosomes. Autophagy receptors bind to LC3/GABARAP proteins on phagophore and autophagosome membranes, and recognize signals on cargoes to deliver them to autophagy. Ubiquitin (Ub), a well-known signal for the degradation of polypeptides in the proteasome, also plays an important role in the recognition of cargoes destined for selective autophagy. In addition, a variety of cargoes are committed to selective autophagy pathways by Ub-independent mechanisms employing protein–protein interaction motifs, Ub-like modifiers, and sugar- or lipid-based signals. In this article we summarize Ub-dependent and independent selective autophagy pathways, and discuss regulatory mechanisms and challenges for future studies.
A new class of transcripts, long noncoding RNAs (lncRNAs), has been recently found to be pervasively transcribed in the genome. Multiple lines of evidence increasingly link mutations and dysregulations of lncRNAs to diverse human diseases. Alterations in the primary structure, secondary structure, and expression levels of lncRNAs as well as their cognate RNA-binding proteins underlie diseases ranging from neurodegeneration to cancer. Recent progress suggests that the involvement of lncRNAs in human diseases could be far more prevalent than previously appreciated. We review the evidence linking lncRNAs to diverse human diseases and highlight fundamental concepts in lncRNA biology that still need to be clarified to provide a robust framework for lncRNA genetics.
Highlights • Integrins contribute to cancer progression via adhesion-dependent and -independent pathways. • Specific integrins not only represent stem cell markers, but also dictate stem cell behavior. • Integrins drive therapeutic resistance through canonical and non-canonical mechanisms. • Integrin expression contributes to multiple steps of the metastatic cascade.
Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species (ROS), particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.
3D cell-culture models have recently garnered great attention because they often promote levels of cell differentiation and tissue organization not possible in conventional 2D culture systems. We review new advances in 3D culture that leverage microfabrication technologies from the microchip industry and microfluidics approaches to create cell-culture microenvironments that both support tissue differentiation and recapitulate the tissue–tissue interfaces, spatiotemporal chemical gradients, and mechanical microenvironments of living organs. These ‘organs-on-chips’ permit the study of human physiology in an organ-specific context, enable development of novel in vitro disease models, and could potentially serve as replacements for animals used in drug development and toxin testing.
MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs, which regulate complementary mRNAs by inducing translational repression and mRNA decay. Although this dual repression system seems to operate in both animals and plants, genetic and biochemical studies suggest that the mechanism underlying the miRNA-mediated silencing is different in the two kingdoms. Here, we review the recent progress in our understanding of how miRNAs mediate translational repression and mRNA decay, and discuss the contributions of the two silencing modes to the overall silencing effect in both kingdoms.
Highlights • mTORC1 activity requires the Rag and Rheb GTPases and signals from amino acids and growth factors. • Growth factor-stimulated PI3K–Akt signaling activates Rheb and mTORC1 at the lysosome. • Amino acid signaling promotes mTORC1–Rheb colocalization at the lysosome. • Akt activates Rheb by inducing dissociation of its GAP, the TSC complex, from the lysosome.
Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders. Phase separation is known to play a role in a variety of cellular processes, including formation of classical membraneless organelles, signaling complexes, the cytoskeleton, and numerous other supramolecular assemblies. The concept of phase separation provides a new framework for our understanding of the functional role of sequence degeneracy (low-complexity) and protein disorder. Accumulating evidence points to a key role for phase transitions in human diseases associated with protein aggregation, and to the misregulation of membraneless organelles in disease. Understanding the physical principles and molecular interactions behind protein phase separation could inspire novel biomaterials.
Highlights • The TME significantly influences therapeutic response. • Contributions from the TME can both abrogate and enhance the efficacy of therapeutic interventions. • Both pre-existing and therapy-induced mechanisms are instrumental to this effect. • Re-educating the TME could help to increase therapeutic efficacy.
Highlights • Cells possess a complex proteostasis network (PN) to ensure protein homeostasis. • Aggregates permanently engage molecular chaperones and other PN components. • The PN is challenged by chronic stress in protein-aggregation diseases and aging. • Overtaxing the PN drives a vicious cycle of disease progression with eventual proteostasis collapse.