Kevin M. Ryan

Cancer cells proliferate rapidly and require sustained supplies of nutrients and biosynthetic precursors. Lysosomes are more than terminal degradation sites: they recycle amino acids, sugars, lipids, nucleosides and ions, while also coordinating nutrient sensing, organelle communication and immune regulation. Consequently, lysosomal capacity can become selectively advantageous in tumours by linking nutrient salvage with growth control, organelle communication and inflammatory signalling. Enhanced lysosomal function can support tumour growth, invasion and therapy resistance. Here, we review four cancer‐relevant dimensions of lysosomal capacity: catabolism and transport; mTORC1‐ and AMPK‐linked nutrient sensing; membrane contact sites with the ER, mitochondria, and Golgi; and immune regulation spanning innate and adaptive responses and inflammatory control. These functions are context dependent: lysosomal quality control can restrain tumour initiation, whereas established cancers often exploit increased lysosomal capacity to support proliferation, invasion, metastasis and therapy resistance. Finally, we discuss lysosome‐state biomarkers and lysosome‐targeted strategies for patient stratification and rational combination therapy.

Macroautophagy (hereafter referred to as autophagy) plays a key role in maintaining cellular homeostasis and shaping response to stress and inflammation. We outline here that inflammatory cytokines trigger caspase-8-dependent cleavage of the autophagy adaptor protein p62/SQSTM1 at aspartic acid 329 generating a truncated form (tr-p62). Tr-p62 enhanced TNF-induced cell death by stabilizing the RIPK1-dependent complex-IIb and amplifying caspase-8 activation, while having no detectable effect on necroptosis. Blocking autophagy leads to tr-p62 accumulation and increased TNF-induced cell death, while non-cleavable p62 reduced autophagic responses and TNF sensitivity. Interestingly, mice naturally lack the caspase-8 cleavage site in p62 and restoring a cleavable version of p62 sensitized mouse cells to TNF-induced cell death. In addition, mice with cleavable p62 showed heightened sensitivity to TNF-induced toxic shock and chemical colitis in vivo. These findings identify p62 cleavage as a key regulator linking autophagy to TNF-driven inflammatory cell death and highlight an important species-specific difference that may influence the interpretation of inflammatory disease models.Abbreviation: DSS: dextran sulfate sodium; FADD: Fas-associated death domain protein; LC3: microtubule-associated protein 1A/1B-light chain 3; PROTAC: proteolysis-targeting chimera; RIPK1: receptor-interacting serine/threonine-protein kinase 1; SMAC: second mitochondria-derived activator of caspases; TNF: tumour necrosis factor; TRAIL: TNF-related apoptosis-inducing ligand.

After years of hard work, publishing your manuscript is a critical part of the scientific process to tell others about your findings, to allow scrutiny of your results and in addition, to show your capabilities as a scientist, helping forward your career. Often, however, the process is fraught with rejection, frustration and upset. Within this short editorial, we highlight a few suggestions and initiatives that we hope will make the process of publishing easier and more efficient.

Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis as early‐stage asymptomaticity leads to late‐stage diagnoses. Strategies to detect PDAC earlier or identify high‐risk individuals are therefore paramount. Here, we report results from genetically engineered mice and PDAC patients that identify serum proteins associated with pancreatic intraepithelial neoplasms (PanINs), the most common PDAC precursor, and early‐stage PDAC. Initially, we screened previously described PanIN‐abundant mice, harbouring pancreatic and duodenal homeobox 1 ( Pdx1 ) ‐Cre , Lox‐STOP‐Lox‐ Kras ^G12D/+ and floxed alleles of essential autophagy genes autophagy‐related 7 ( Atg7 ) or autophagy‐related 5 ( Atg5 ). Sera from these mice were assessed by proteomics and hits were compared to those in Lox‐STOP‐Lox‐ Kras ^G12D/+ Lox‐STOP‐Lox‐ Trp53 ^R172H/+ Pdx1‐Cre (KPC) mice, which closely recapitulate human disease, and early‐stage (I–II) PDAC patients. Levels of inter‐alpha‐trypsin inhibitor heavy chain H3 (ITIH3) were significantly elevated in all three screens, with complement C5, complement factors B and H (CFB/CFH), and monocyte differentiation antigen CD14 increased in KPC mice and PDAC patients; and all were significantly increased co‐ordinately in PDAC according to disease stage. Serum levels of C5, CFH and CD14 together constitute a novel panel for identifying PanINs and early‐stage PDAC with confidence, and when combined with additional screening, could help increase survival from this dismal disease.

Cells harness multiple pathways to maintain lysosome integrity, a central homeostatic process. Damaged lysosomes can be repaired or targeted for degradation by lysophagy, a selective autophagy process involving ATG8/LC3. Here, we describe a parallel ATG8/LC3 response to lysosome damage, mechanistically distinct from lysophagy. Using a comprehensive series of biochemical, pharmacological, and genetic approaches, we show that lysosome damage induces non-canonical autophagy and Conjugation of ATG8s to Single Membranes (CASM). Following damage, ATG8s are rapidly and directly conjugated onto lysosome membranes, independently of ATG13/WIPI2, lipidating to PS (and PE), a molecular hallmark of CASM. Lysosome damage drives V-ATPase V0-V1 association, direct recruitment of ATG16L1 via its WD40-domain/K490A, and is sensitive to Salmonella SopF. Lysosome damage-induced CASM is associated with formation of dynamic, LC3A-positive tubules, and promotes robust LC3A engagement with ATG2, a lipid transfer protein central to lysosome repair. Together, our data identify direct ATG8 conjugation as a rapid response to lysosome damage, with important links to lipid transfer and dynamics.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson’s disease (PD), with growing importance also for Crohn’s disease and cancer. LRRK2 is a large and complex protein possessing both GTPase and kinase activity. Moreover, LRRK2 activity and function can be influenced by its phosphorylation status. In this regard, many LRRK2 PD-associated mutants display decreased phosphorylation of the constitutive phosphorylation cluster S910/S935/S955/S973, but the role of these changes in phosphorylation status with respect to LRRK2 physiological functions remains unknown. Here, we propose that the S910/S935/S955/S973 phosphorylation sites act as key regulators of LRRK2-mediated autophagy under both basal and starvation conditions. We show that quadruple LRRK2 phosphomutant cells (4xSA; S910A/S935A/S955A/S973A) have impaired lysosomal functionality and fail to induce and proceed with autophagy during starvation. In contrast, treatment with the specific LRRK2 kinase inhibitors MLi-2 (100 nM) or PF-06447475 (150 nM), which also led to decreased LRRK2 phosphorylation of S910/S935/S955/S973, did not affect autophagy. In explanation, we demonstrate that the autophagy impairment due to the 4xSA LRRK2 phospho-dead mutant is driven by its enhanced LRRK2 kinase activity. We show mechanistically that this involves increased phosphorylation of LRRK2 downstream targets Rab8a and Rab10, as the autophagy impairment in 4xSA LRRK2 cells is counteracted by expression of phosphorylation-deficient mutants T72A Rab8a and T73A Rab10. Similarly, reduced autophagy and decreased LRRK2 phosphorylation at the constitutive sites were observed in cells expressing the pathological R1441C LRRK2 PD mutant, which also displays increased kinase activity. These data underscore the relation between LRRK2 phosphorylation at its constitutive sites and the importance of increased LRRK2 kinase activity in autophagy regulation and PD pathology.

The formation of organisations and societies within all areas of scientific research facilitates the bringing together of researchers in a given field and serves to aid communication, collaboration, progress of science and career development. Even greater gain can be attained when individual organisations form partnerships to complement each other's activities and to increase the scope of their endeavours. Within this editorial, we highlight the key points of a new partnership formed between two non-profit bodies within cancer research, the European Association for Cancer Research (EACR) and Molecular Oncology, a journal wholly owned by the Federation of European Biochemical Societies (FEBS).