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.

Secretory autophagy during lysosome inhibition (SALI).

Both macroautophagy/autophagy and extracellular vesicle (EV) secretion pathways converge upon the endolysosome system. Although lysosome impairment leads to defects in autophagic degradation, the impact of such dysfunction on EV secretion remains poorly understood. Recently, we uncovered a novel secretory autophagy pathway that employs EVs and nanoparticles (EVPs) for the secretion of autophagy cargo receptors outside the cell when either autophagosome maturation or lysosomal function is blocked.

The Autophagy, Inflammation and Metabolism Center international eSymposium - an early-career investigators' seminar series during the COVID-19 pandemic.

The Autophagy, Inflammation and Metabolism (AIM) Center organized a globally accessible, virtual eSymposium during the COVID-19 pandemic in 2020. The conference included presentations from scientific leaders, as well as a career discussion panel, and provided a much-needed platform for early-career investigators (ECIs) to showcase their research in autophagy. This Perspective summarizes the science presented by the ECIs during the event and discusses the lessons learned from a virtual meeting of this kind during the pandemic.

Cancers associated with human gammaherpesviruses.

Epstein-Barr virus (EBV; human herpesvirus 4; HHV-4) and Kaposi sarcoma-associated herpesvirus (KSHV; human herpesvirus 8; HHV-8) are human gammaherpesviruses that have oncogenic properties. EBV is a lymphocryptovirus, whereas HHV-8/KSHV is a rhadinovirus. As lymphotropic viruses, EBV and KSHV are associated with several lymphoproliferative diseases or plasmacytic/plasmablastic neoplasms.

Autophagy in host stromal fibroblasts supports tumor desmoplasia.

Growing evidence demonstrates that macroautophagy/autophagy in the host stroma influences the tumor microenvironment. We have uncovered that autophagy in host stromal fibroblasts is compulsory to initiate and maintain the desmoplastic fibrotic response that fosters mammary tumor progression. Genetic loss of fibroblast autophagy impedes COL1A/type 1 collagen secretion, which is required for the development of a stiff tissue matrix permissive for mammary tumor growth.

Atg32-dependent mitophagy sustains spermidine and nitric oxide required for heat-stress tolerance in Saccharomycescerevisiae.

In Saccharomyces cerevisiae, the selective autophagic degradation of mitochondria, termed mitophagy, is critically regulated by the adapter protein Atg32. Despite our knowledge about the molecular mechanisms by which Atg32 controls mitophagy, its physiological roles in yeast survival and fitness remains less clear. Here, we demonstrate a requirement for Atg32 in promoting spermidine production during respiratory growth and heat-induced mitochondrial stress.

Emerging roles for the autophagy machinery in extracellular vesicle biogenesis and secretion.

Autophagy classically functions to maintain cell health during stressful conditions by targeting cytosolic components for degradation and recycling via lysosomal pathways. However, accumulating evidence also supports roles for autophagy-related genes (ATGs) in non-degradative processes including cellular secretion. Here, we review emerging roles for the autophagy machinery in regulating extracellular vesicle loading and secretion and discuss how functional coupling of these pathways may impact normal physiology and disease.

Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.

Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal.

The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets.

The huge cadre of genes regulated by Myc has obstructed the identification of critical effectors that are essential for Myc-driven tumorigenesis. Here, we describe how only the lack of the receptor Fzd9, previously identified as a Myc transcriptional target, impairs sustained tumor expansion and β-cell dedifferentiation in a mouse model of Myc-driven insulinoma, allows pancreatic islets to maintain their physiological structure and affects Myc-related global gene expression. Importantly, Wnt signaling inhibition in Fzd9-competent mice largely recapitulates the suppression of proliferation caused by Fzd9 deficiency upon Myc activation.

Beyond Autophagy: The Expanding Roles of ATG8 Proteins.

The ATG8 family proteins are critical players in autophagy, a cytoprotective process that mediates degradation of cytosolic cargo. During autophagy, ATG8s conjugate to autophagosome membranes to facilitate cargo recruitment, autophagosome biogenesis, transport, and fusion with lysosomes, for cargo degradation. In addition to these canonical functions, recent reports demonstrate that ATG8s are also delivered to single-membrane organelles, which leads to highly divergent degradative or secretory fates, vesicle maturation, and cargo specification.

The pleiotropic functions of autophagy in metastasis.

Autophagy is deregulated in many cancers and represents an attractive target for therapeutic intervention. However, the precise contributions of autophagy to metastatic progression, the principle cause of cancer-related mortality, is only now being uncovered. While autophagy promotes primary tumor growth, metabolic adaptation and resistance to therapy, recent studies have unexpectedly revealed that autophagy suppresses the proliferative outgrowth of disseminated tumor cells into overt and lethal macrometastases.

LC3-dependent extracellular vesicle loading and secretion (LDELS).

Accumulating evidence implicates various autophagy-related (ATG) proteins in cellular secretion. Recently, we identified a new secretory autophagy pathway in which components of LC3 conjugation machinery specify the incorporation of RNA binding proteins (RBPs) and small non-coding RNAs into extracellular vesicles (EVs), resulting in their secretion outside of cells. We term this process C3-ependent V oading and ecretion (LDELS).

Autophagy suppresses breast cancer metastasis by degrading NBR1.

Macroautophagy/autophagy plays complex, context-dependent roles in cancer. How autophagy governs the emergence of metastatic disease has been incompletely understood. We recently uncovered that genetic autophagy inhibition strongly attenuates primary tumor growth in mammary cancer models, yet paradoxically promotes spontaneous metastasis to the lung and enables the outgrowth of disseminated tumor cells (DTCs) into overt macro-metastases.

Unraveling the mechanisms that specify molecules for secretion in extracellular vesicles.

Extracellular vesicles (EVs) are small membrane-bound organelles naturally released from cells and potentially function as vehicles of intercellular communication. Cells release numerous sub-species of EVs, including exosomes and microvesicles, which are formed via distinct cellular pathways and molecular machineries and contain specific proteins, RNAs and lipids. Accumulating evidence indicates that the repertoire of molecules packaged into EVs is shaped by both the physiological state of the cell and the EV biogenesis pathway involved.

The LC3-conjugation machinery specifies the loading of RNA-binding proteins into extracellular vesicles.

Traditionally viewed as an autodigestive pathway, autophagy also facilitates cellular secretion; however, the mechanisms underlying these processes remain unclear. Here, we demonstrate that components of the autophagy machinery specify secretion within extracellular vesicles (EVs). Using a proximity-dependent biotinylation proteomics strategy, we identify 200 putative targets of LC3-dependent secretion.

Autophagy and the cell biology of age-related disease.

Macroautophagy (autophagy) is a conserved lysosomal degradation process essential for cellular homeostasis and adaption to stress. Accumulating evidence indicates that autophagy declines with age and that impaired autophagy predisposes individuals to age-related diseases, whereas interventions that stimulate autophagy often promote longevity. In this Review, we examine how the autophagy pathway restricts cellular damage and degeneration, and the impact of these functions towards tissue health and organismal lifespan.

An ATG16L1-dependent pathway promotes plasma membrane repair and limits Listeria monocytogenes cell-to-cell spread.

Plasma membrane integrity is essential for the viability of eukaryotic cells. In response to bacterial pore-forming toxins, disrupted regions of the membrane are rapidly repaired. However, the pathways that mediate plasma membrane repair are unclear.

WIPIng the Brakes off Autophagy Induction.

In this issue of Molecular Cell, Wan et al. (2018) uncover WIPI2 as a critical rheostat in the control of autophagic degradation by mTORC1 and demonstrate the physiological utility of this signaling axis in promoting the clearance of hepatic lipids.

Atg12-Atg3 Coordinates Basal Autophagy, Endolysosomal Trafficking, and Exosome Release.

We recently identified an interaction between Atg12-Atg3, a complex between 2 core autophagy regulators, and the ESCRT-associated protein Pdcd6ip (programmed cell death 6 interacting protein, commonly known as Alix), which coordinately regulates basal autophagy, late endosome-to-lysosome trafficking, and exosome release. Because these processes all serve fundamental roles in cancer progression and therapy, Atg12-Atg3 may be an attractive anticancer target.

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.

Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED).

Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins.

The identification of conserved autophagy-related proteins (ATGs) that mediate bulk degradation of cytosolic material laid the foundation for breakthroughs linking autophagy to a litany of physiological processes and disease conditions. Recent discoveries are revealing that these same ATGs orchestrate processes that are related to, and yet clearly distinct from, classic autophagy. Autophagy-related functions include secretion, trafficking of phagocytosed material, replication and egress of viral particles, and regulation of inflammatory and immune signaling cascades.