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Bose, P.

Publications and source records attributed to Bose, P..

At least 19 recordsLinked to original sources

Vape Aerosol Exposure Decreases Voluntary Exercise in Mice

Electronic cigarette use (vaping) is generally accepted as a less harmful alternative to traditional cigarette smoking. However, so called "never smokers" including young adults and teenagers are often recruited through targeted advertising and appealing vape juice flavors. Any fitness cost of vaping matters for young people who exercise or play sports. We therefore tracked running distance in a mouse model of voluntary exercise to assess the effect of vaping. Specifically, we asked whether vaping decreases exercise performance, and whether there is progressive change over time. Experimental groups of mice subjected to whole-body inhalation exposure and corresponding non-exposed controls were housed in cages with running wheels. Daily wheel laps were recorded over the 8-week exposure period and analyzed using hierarchical generalized additive mixed models. Vape-exposed females ran 32% fewer laps than control females. Vape-exposed males showed a smaller reduction of 15% that did not reach statistical significance. The reduction was 10,025 laps per day larger in females than in males (p = 0.02). In females, the difference was present from the first weeks of exposure and was larger by the end of the study. The results demonstrate that vape exposure is associated with reduced voluntary aerobic activity. The analysis illustrates how nonlinear longitudinal modeling clarifies both the size and the temporal character of treatment effect in this experimental model. These findings reveal that nicotine-free components of vape aerosol reduce voluntary aerobic activity, highlighting an overlooked facet of vaping toxicity research which is particularly relevant for young and physically active users.

pharmacology and toxicology↗

PIAS1 loss and INHBA gain define a TGFβ-driven EMT state in OSCC progression

Oral squamous cell carcinoma (OSCC), a highly aggressive subtype of head and neck cancer, remains a major clinical challenge with limited therapeutic options and poor survival outcomes. The Protein Inhibitor of Activated STAT1 (PIAS1), a SUMO E3 ligase involved in transcriptional regulation, DNA repair, and epithelial-mesenchymal transition (EMT), exhibits cancer type-specific roles, but its function in OSCC has not been well characterized. Here, we investigated the molecular and functional role of PIAS1 in OSCC progression and prognosis. All patient cohorts analysed here comprise HPV-negative disease. Analysis across multiple cohorts revealed that PIAS1 mRNA expression is significantly lower in tumor tissues than in normal oral cavity squamous epithelium, including in a cohort of 60 patient-matched tumor and normal pairs. Within the tumor compartment, protein abundance of PIAS1 correlated positively with patient survival. Functional assays using OSCC cell lines demonstrated that PIAS1 acts in a SUMO E3-dependent manner to suppress TGF{beta}-induced migration and invasion. Transcriptomic profiling of PIAS1-depleted cells revealed alterations in expression of genes with relevance in TGF{beta} signaling and pro-invasive cellular responses. Further analyses showed that 46 of these differentially altered hits intersected with The Cancer Genome Atlas (TCGA)-OSCC datasets, where four of these genes, including INHBA, associated with cell stemness-pathway. Spatial analysis of the mRNA abundance of INHBA within OSCC-derived surgical specimens showed increased abundance at the invasive front, and positively associated with aggressive tumor phenotypes, poor patients' outcomes, and resistance to immunotherapy. Single-cell RNA-seq analyses of INHBA revealed increased levels within tumor cells and cancer-associated fibroblasts (CAFs), suggesting potential tumor-intrinsic and extrinsic (tumor microenvironment) sources and hence actions. Collectively, our findings establish PIAS1 as a tumor suppressor in OSCC that restrains TGF{beta}-driven aggressive behaviour. Furthermore, we identify INHBA as a potential therapeutic target, among other genes characterized by spatially restricted, invasive tumor phenotypes.

cancer biology↗

Synthetic analogue of adrenocorticotropic hormone, ACTH(4-7)PGP delays neurological manifestations in diseases of mucopolysaccharidosis III spectrum by reducing neuroinflammation and rescuing neurotransmission, synaptogenesis, and axonal demyelination

Mucopolysaccharidosis III (MPS III or Sanfilippo disease) is a spectrum of 4 genetic disorders (MPS IIIA-D), caused by defects in the genes SGSH, NAGLU, HGSNAT and GNS encoding enzymes involved in degradation of heparan sulfate (HS). HS accumulates in brain tissues and causes neuronal dysfunction and neurodegeneration leading to neuropsychiatric problems, developmental delays, childhood dementia, blindness and death during the second decade of life. Previously, we demonstrated that pathophysiological mechanisms, underlying MPS IIIC in mouse models, involves functional pathological changes, affecting synaptogenesis and synaptic transmission and leading to learning and memory deficits. These results suggested that a treatment for MPS III could be developed by using compounds inducing synaptogenesis. In the current study, we tested the efficacy of a synthetic peptide ACTH(4-7)PGP, an analog of adrenocorticotropic hormone fragment, previously used as a neuroprotective and anti-inflammatory medication for treatment of acute neurological conditions, including stroke. We show that intranasal administration of ACTH(4-7)PGP restores defective synaptic transmission in CA1 pyramidal neurons of MPS IIIA and MPS IIIC mouse models and rescues the decrease in synaptic proteins in cultured MPS IIIC mouse hippocampal neurons and iPSC-derived neurons of human MPS IIIA, MPS IIIB and MPS IIIC patients. Furthermore, daily intranasal administration of ACTH(4-7)PGP to MPS IIIC and MPS IIIA mice reduces hyperactivity and rescues defects in working and spatial memory, delays progression of CNS pathology including neuroinflammation and axonal demyelination, and increases the lifespan. Together with the absence of any adverse reactions to ACTH(4-7)PGP in the MPS III and WT mice, our results justify testing the drugs efficacy in clinical settings.

genetics↗

Eukaryotic Initiation Factor 5B (eIF5B)-Driven Translational Control Impacts Oral Squamous Cell Carcinoma Pathophysiology

The non-canonical translation of specific mRNAs has been implicated in oncogenesis and cancer progression. We previously identified eukaryotic Initiation Factor 5B (eIF5B) as a key factor in Internal Ribosome Entry Site (IRES)-mediated translation of a subset of mRNAs encoding anti-apoptotic proteins. Here, we demonstrate that EIF5B is predominantly expressed in cancer cells compared to other cell types in the Oral Squamous Cell Carcinoma (OSCC) microenvironment. Higher EIF5B mRNA and protein expression are associated with poor patient outcomes. We show that eIF5B depletion in OSCC cells blunted pro-growth, pro-inflammatory, and pro-angiogenic signaling pathways and significantly increased TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death. This is achieved through decreased translation of mRNAs encoding critical factors associated with OSCC pathophysiology. Importantly, the level of interaction of eIF5B with tRNAiMet was significantly higher in OSCC cells compared to non-cancerous fibroblasts. This suggests that OSCC cells (but not non-cancerous fibroblasts) rely heavily on eIF5B for translation initiation. In an in vivo flank xenograft model using nude mice, eIF5B knockdown in UMSCC-29 cells led to a significant reduction in tumor volume compared to control tumors. Also, the immunohistochemical analysis of the xenografted tumor sections demonstrated decreased staining intensity of critical factors associated with OSCC pathophysiology in eIF5B-depleted tumors relative to controls. Collectively, our data demonstrate that OSCC cells are uniquely dependent on eIF5B-tRNA interactions to sustain translation of pro-survival mRNAs. Targeting eIF5B disrupts these oncogenic programs, sensitizing OSCC cells to apoptosis and suppressing pro-angiogenic and pro-growth signaling.

cancer biology↗

The Elg1 Replication Factor C-like complex safeguards cells from replication stress through a noncanonical pathway independent of the Mec1-Rad53 axis

The Elg1 Replication Factor C-like complex (Elg1-RLC) that functions as a PCNA unloader, is known to be involved in multiple DNA replication/repair-related activities from yeast to humans. By exploiting disassembly-prone PCNA mutants, we reveal that Elg1-RLC uses its PCNA unloading activity to counter the DNA-alkylating agent methyl-methanesulfonate (MMS)-mediated slow progression of replication forks. Despite having a largely functional DNA Damage Response (DDR), the viability loss of elg1{Delta}-DDR double mutants, in the presence of MMS, matches that of mec1{Delta} and rad53{Delta} cells, deficient for the central checkpoint kinases. This suggests that elg1{Delta}-DDR double mutants experience replication fork collapse when exposed to MMS. Indeed, in response to MMS, accumulation of Rad52 foci in the replicative elg1{Delta}-DDR cells supports this possibility. However, the failure of rescuing elg1{Delta}-DDR mutants by elevating dNTP levels (by deleting the ribonucleotide reductase SML1) eliminates the possibility of a Rad53-regulated dNTP shortage-mediated fork collapse. Thus, we propose a S-phase checkpoint regulatory role of Elg1-RLC that works through a noncanonical pathway parallel to the canonical one. Collectively, our findings suggest a model in which Elg1-RLC, by timely unloading chromatin-bound PCNA from the damaged/stalled forks, coordinates the DDR pathways to safeguard the integrity of replication forks under replication stress.

molecular biology↗

Spatially resolved single-cell analysis uncovers protein kinase C-& expressing microglia with anti-tumor activity in glioblastoma

Glioblastoma (GBM) is a brain tumor that poses a formidable challenge to treatment options available. The tumor microenvironment (TME) in GBM is highly complex, marked by immunosuppression and cellular heterogeneity. Understanding the cellular interactions and their spatial organization within the TME is crucial for developing effective therapeutic strategies. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics in a GBM mouse model to unravel the spatial landscape of the brain TME. We identified a previously unrecognized microglia subtype expressing protein kinase C{delta} (PKC{delta}) associated with potent anti-tumor functions. The presence of PKC{delta}-expressing microglia was confirmed in resected human GBM specimens. Elevating tumoral PKC{delta} expression using niacin or adeno-associated virus in mice enhanced the phagocytosis of GBM cells by microglia in culture and increased the lifespan of mice with intracranial GBM. These findings were corroborated in analyses of the TCGA GBM datasets where low PKC{delta} samples showed negative pathway enrichment for apoptosis, phagocytosis, and immune signaling pathways, as well as lower levels of immune cell infiltration overall. Our study underscores the importance of integrating spatial context to unravel the TME, resulting in the identification of previously unrecognized subsets of microglia with anti-tumor functions. These findings provide valuable insights for advancing innovative immunotherapeutic strategies in GBM.

immunology↗

Revealing Molecular Mechanisms of Early-Onset Tongue Cancer by Spatial Transcriptomics

Tongue cancer at a young age demonstrates an increase in incidence, aggressiveness, and poor response to therapy. Classic etiological factors for head and neck tumors such as tobacco, alcohol, and human papillomavirus are not related to early-onset tongue cancer. Mechanisms of development and progression of this cancer remain unclear. In this study, we performed spatial whole-transcriptome profiling of tongue cancer in young adults compared with elderly patients. Oxidative stress, vascular mimicry, and MAPK and JAK-STAT pathways were enriched in early-onset tongue cancer. Tumor microenvironment demonstrated increased gene signatures corresponding to myeloid-derived suppressor cells, tumor-associated macrophages, and plasma cells. The invasive front was accompanied by vascular mimicry with arrangement of tumor-associated macrophages and aggregations of plasma cells and lymphocytes organized into tertiary lymphoid structures. Taken together, these results indicate that early-onset tongue cancer has distinct spatial transcriptomic features and molecular mechanisms compared to older patients. HIGHLIGHTSO_LIEarly-onset tongue cancer demonstrates extremely downregulated oxidative phosphorylation and upregulated glycolysis. C_LIO_LIMAPK pathway is the key player in the pathogenesis of tongue cancer in young adults. C_LIO_LIEarly-onset tongue cancer is characterized by JAK-STAT dependent vascular mimicry supported by tumor-associated macrophages at the invasive edge. C_LIO_LITongue cancer microenvironment in young adults enriches for immunosuppressive myeloid derived suppressor cells and demonstrates reduced antigen presentation function. C_LIO_LIThe tumor border in early-onset tongue cancer is enriched with plasma cells and lymphocytes in tertiary lymphoid structures. C_LI

cancer biology↗

Single cell spatial analysis identifies regulators of brain tumor initiating cells

Glioblastomas (GBMs) are aggressive brain tumors with extensive intratumoral heterogeneity. Here, we used spatial transcriptomics and single-cell ATAC-seq to dissect the transcriptome of distinct anatomical regions of the tumor microenvironment. We identified numerous extracellular matrix (ECM) molecules including biglycan elevated in areas infiltrated with brain tumor-initiating cells (BTICs). Single-cell RNA sequencing showed that the ECM molecules were differentially expressed by cells including injury response versus developmental BTICs. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, and this was associated mechanistically with LDL receptor-related protein 6 (LRP6) binding and activation of the Wnt/{beta}-catenin pathway. Biglycan-overexpressing BTICs grew to a larger tumor mass when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in the GBM microenvironment and suggests biglycan-LRP6 axis as a therapeutic target to curb GBM growth.

cancer biology↗

Spatial transcriptomics reveals distinct and conserved tumor core and edge architectures that predict survival and targeted therapy response

We performed the first integrative single-cell and spatial transcriptomic analysis on HPV-negative oral squamous cell carcinoma (OSCC) to comprehensively characterize tumor core (TC) and leading edge (LE) transcriptional architectures. We show that the TC and LE are characterized by unique transcriptional profiles, cellular compositions, and ligand-receptor interactions. We demonstrate that LE regions are conserved across multiple cancers while TC states are more tissue specific. Additionally, we found our LE gene signature is associated with worse clinical outcomes while the TC gene signature is associated with improved prognosis across multiple cancer types. Finally, using an in silico modeling approach, we describe spatially-regulated patterns of cell development in OSCC that are predictably associated with drug response. Our work provides pan-cancer insights into TC and LE biologies, a platform for data exploration (http://www.pboselab.ca/spatial_OSCC/) and is foundational for developing novel targeted therapies.

cancer biology↗

Ganglioside enriched phospholipid vesicles induce cooperative Aβ oligomerization and membrane disruption

A major hallmark of Alzheimer disease (AD) is the accumulation of extracellular aggregates of amyloid-{beta} (A{beta}). Structural polymorphism observed among A{beta} fibrils in AD brains seem to correlate with the clinical sub-types suggesting a link between fibril polymorphism and pathology. Since fibrils emerge from a templated growth of low-molecular weight oligomers, understanding the factors affecting oligomer generation is important. The membrane lipids are key factors that influence early stages of A{beta} aggregation and oligomer generation, and cause membrane disruption. We have previously demonstrated that conformationally discrete A{beta} oligomers can be generated by modulating the charge, composition, chain length of lipids and surfactants. Here, we extend our studies into liposomal models by investigating A{beta} oligomerization on large unilamellar vesicles (LUVs) of total brain extracts (TBE), reconstituted lipid rafts (LRs) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC). Specifically, we varied the vesicle composition by varying the amount of GM1 gangliosides added as a constituent. We found that liposomes enriched in GM1 induce the formation of toxic, low-molecular weight oligomers that are isolable in a lipid-complexed form. Importantly, the data indicate that oligomer formation and membrane disruption are highly cooperative processes. Numerical simulations on the experimental data confirm cooperativity and reveal that GM1-enriched liposomes form twice as many numbers of pores as those without GM1. Overall, this study uncovers mechanisms of cooperativity between oligomerization and membrane disruption under controlled lipid compositional bias, and refocuses the significance of the early stages of A{beta} aggregation in polymorphism, propagation, and toxicity in AD. TOC figure O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

biophysics↗

Fundamentals of Vaping-Associated Pulmonary Injury Leading to Severe Respiratory Distress

Vaping of flavored liquids has been touted as safe alternative to traditional cigarette smoking with decreased health risks. The popularity of vaping has dramatically increased over the last decade, particularly among teenagers who incorporate vaping into their daily life as a social activity. Despite widespread and increasing adoption of vaping among young adults there is little information on long term consequences of vaping and potential health risks. This study demonstrates Vaping-Induced Pulmonary Injury (VAPI) using commercial JUUL pens with flavored vape juice using an inhalation exposure murine model. Profound pathological changes to upper airway, lung tissue architecture, and cellular structure are evident within 9 weeks of exposure. Marked histologic changes include increased parenchyma tissue density, cellular infiltrates proximal to airway passages, alveolar rarefaction, increased collagen deposition, and bronchial thickening with elastin fiber disruption. Transcriptional reprogramming includes significant changes to gene families coding for xenobiotic response, glycerolipid metabolic processes, and oxidative stress. Cardiac contractile performance for systemic output is moderately but significantly impaired, and the shows severe pulmonary side structural remodeling with chamber enlargement. This VAPI model with pulmonary circuit failure demonstrates mechanistic underpinnings of vaping-related pathologic injury.

molecular biology↗

Oral Glucosamine Ameliorates Aggravated Neurological Phenotype in Mucopolysaccharidosis III Type C Mouse Model Expressing Misfolded HGSNAT Variant

ObjectiveOver 55% of mucopolysaccharidosis IIIC (MPS IIIC) patients have at least one allelic missense variant responsible for misfolding of heparan sulfate acetyl-CoA:-glucosaminide N- acetyltransferase (HGSNAT). These variants are potentially treatable with pharmacological chaperones, such as a competitive HGSNAT inhibitor, glucosamine. Since the constitutive HGSNAT knockout mice, we generated previously cannot be used to test such strategy in vivo, we generated a novel model, the HgsnatP304L strain, expressing misfolded mutant HGSNAT with human missense mutation Pro311Leu (Pro304Leu in the mouse enzyme). ResultsHgsnatP304L mice present deficits in short-term (novel object recognition test) and working/spatial (Y-maze test) memory at 4 months of age, 2-4 months earlier than previously described gene-targeted Hgsnat-Geo mice, which lack HGSNAT protein. HgsnatP304L mice also show increased severity of synaptic deficits in CA1 neurons, and accelerated course of CNS pathology including neuronal storage of heparan sulfate, accumulation of misfolded proteins, increase of simple gangliosides, and neuroinflammation as compared with Hgsnat-Geo mice. Expression of misfolded human Pro311Leu HGSNAT protein in cultured hippocampal Hgsnat- Geo neurons aggravated reduction of synaptic proteins. Memory deficits and majority of pathological changes in the brain were rescued in mice receiving daily doses of oral glucosamine. InterpretationAltogether, our data for the first time demonstrate dominant-negative effects of the misfolded HGSNAT Pro304Leu variant and show that these effects are treatable by oral administration of glucosamine, suggesting that patients, affected with missense mutations preventing normal folding of the enzyme, could benefit from chaperone therapy.

animal behavior and cognition↗

Compensatory changes in contralesional node strength, brain wide modularity and cross-modular functional interactions in a rat model of traumatic brain injury

Penetrating cortical impact injuries alter neuronal communication beyond the injury epicenter, across regions involved in affective, sensorimotor, and cognitive processing. Understanding how traumatic brain injury (TBI) reorganizes local and brain wide nodal functional interactions may provide valuable quantitative parameters for monitoring pathological progression and functional recovery. To this end, we investigated spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal obtained at 11.1 Tesla in rats sustaining controlled cortical impact (CCI) and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12,879 pairwise correlations between fMRI signals from 162 regions. Our data indicate that on days 2 and 30 post-CCI there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic, and basal forebrain areas. Rats imaged on day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality, and participation coefficient track early and late TBI effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to CCI may be unfavorable to brain wide communication in the early post-injury period.

neuroscience↗

Clinicopathologic Correlates and Natural History of Atypical Chronic Myeloid Leukemia

There is limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). We evaluated the clinicopathological features, outcomes, and responses to therapy of 65 patients with aCML. Median age was 67 years (range 46-89). The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 tended to appear within dominant clones, with frequent SRSF2 and SETBP1 codominance, while other RAS pathway mutations were more likely to appear as minor clones. Acquisition of new, previously undetectable mutations at transformation was observed in 63% of evaluable patients, the most common involving signaling pathway mutations. Hypomethylating agents were associated with the highest response rates and duration. With a median overall survival of 25 months (95% CI 20-30), intensive chemotherapy was associated with worse OS than other treatment modalities, and allogeneic stem cell transplantation was the only therapy associated with improved outcomes (HR 0.044, 95% CI 0.035-0.593, p=0.007). Age, platelet count, BM blast percentage, and serum LDH levels were independent predictors of survival and were integrated in a multivariable model which allowed to predict 1-year and 3-year survival.

cancer biology↗

Molecular Determinants of Prognosis and Evolution in Diffuse-Lower Grade Astrocytomas

Low grade astrocytomas (LGAs) are classified based on the mutational status of the isocitrate dehydrogenase (IDH) gene. While IDH wild-type (WT) LGAs evolve rapidly to glioblastoma, mutant tumors generally have a more indolent course. To identify potential drivers of the differential progression of LGAs, we analyzed transcriptomes from The Cancer Genome Atlas. Compared to mutant LGAs, platelet-derived growth factor (PDGF) signaling is enriched in WT cases, and PDGFA is the top overexpressed gene in the pathway. Putative mechanisms for differential PDGFA expression included copy number gains of chromosome 7 in WT cases and methylation of the PDGFA promoter in mutant LGAs. Additionally, we found that high PDGFA expression is associated with aneuploidy, immunosuppressive features, and worse prognosis, and that WT LGAs use multiple means to inactivate the p53 pathway to progress to GBM. Our work highlights the contribution of PDGF gene family towards the unique behaviour of LGAs. STATEMENT OF SIGNIFICANCEThis study of gene expression in LGAs suggests that differential regulation of the PDGF pathway may underlie the different natural histories of IDH WT and IDH mutant LGAs including divergent evolutionary trajectories to GBM. This insight may inspire new therapeutic strategies to suppress the transformation of LGAs to higher-grade cancers.

cancer biology↗

Early defects in lysosomal storage diseases disrupt excitatory synaptic transmission

At least two thirds of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPS IIIC, Sanfilippo disease type C) caused by mutations in the HGSNAT gene and lysosomal storage of heparan sulfate the major burden is progressive and severe neuropsychiatric problems, mental retardation, and dementia though to be mainly mediated by neurodegeneration. HGSNAT knockout mice match human clinical phenotype and develop hyperactivity followed by memory impairment and death. In order to understand whether early clinical symptoms in MPS IIIC mice occurring before the onset of massive neurodegeneration are caused by neuronal dysfunction we studied synaptic transmission and morphology in cultured hippocampal and CA1 pyramidal neurons of MPSIIIC mice. Synaptic spines were also studied in other mouse LSD models and postsynaptic densities in post-mortem cortices of human neurological MPS patients. Cultured hippocampal and CA1 pyramidal neurons of MPS IIIC mice showed a drastic decrease or abnormal distribution of multiple pre- and postsynaptic proteins that could be rescued in vitro and in vivo by virus-mediated gene correction. Dendritic spine densities were immature in cultured hippocampal MPS IIIC mouse neurons and reduced in pyramidal neurons of mouse models of MPS IIIC and other (Tay-Sachs, sialidosis) LSD starting from postnatal day 10. MPS IIIC neurons presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganised microtubule network and partially impaired axonal transport of synaptic proteins. Postsynaptic densities were also reduced in post-mortem cotrees of human MPS I, II, IIIA, C and D patients suggesting that the pathology is common for these neurological LSD. Together, our results demonstrate that lysosomal storage causes alterations in synaptic structure and abnormalities in neurotransmission originating from disrupted vesicular transport and preceding the first cognitive symptoms and suggest drugs known to affect synaptic transmission can be potentially applied to treat behavioral and cognitive defects in neurological LSD patients.

neuroscience↗

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

BackgroundThe ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib. MethodsATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined. ResultsThe combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. ConclusionsLung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

cancer biology↗

Immune evasion and immunotherapy resistance via TGF-beta activation of extracellular matrix genes in cancer associated fibroblasts

The ability to disseminate, invade and successfully colonise other tissues is a critical hallmark of cancer that involves remodelling of the extracellular matrix (ECM) laid down by fibroblasts 1. Moreover, Cancer-Associated-Fibroblasts (CAFs) produce key growth factors and cytokines as components of the ECM that fuel tumour growth, metastasis and chemoresistance, and immune response 2-4. ECM changes also predict prognosis in pancreatic 5 and colorectal cancers 6,7. Here, we examine the landscape of ECM-gene dysregulation pan-cancer and find that a subset of ECM genes is (i) dysregulated specifically in cancer, (ii) adversely prognostic, (iii) linked to TGF-beta signalling and transcription in Cancer-Associated-Fibroblasts, (iv) enriched in immunologically active cancers, and (v) predicts responses to Immune checkpoint blockade better than mutation burden, cytolytic activity, or an interferon signature, thus identifying a novel mechanism of immune evasion for patient stratification in precision immunotherapy and pharmacological modulation.

cancer biology↗