Biology subjects

Park, M.

Publications and source records attributed to Park, M..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids

Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FA) and glucose under cold stress but favors FA as the primary fuel for heat production. It remains unclear how BAT steer fuel preference toward FA over glucose. Here we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the {beta}-adrenergic receptor-PKA-PGC-1 axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FA under cold conditions. HighlightsO_LIGot1 is markedly induced by cold in BAT via a {beta}-adrenergic receptor-PKA-PGC-1 axis C_LIO_LIThe increase in cytosolic GOT1 activates the malate-aspartate shuttle (MAS) C_LIO_LIMAS activation promotes fatty acid oxidation while reducing glucose oxidation C_LIO_LILoss of MAS activity in BAT by Got1 deletion shifts the fuel preference to glucose C_LI

cell biology↗

bioRxiv2024

U1 snRNP-Specific U1C Acts as the Gatekeeper of the Survival of Motor Neurons (SMN) Complex in snRNP Biogenesis

The stability and abundance of spliceosomal snRNPs are determined by the assembly of an Sm protein ring (Sm core) on each snRNA, a process facilitated by the survival of motor neuron (SMN) complex. Whereas the SMN complexs role as a chaperone is well-established, the mechanisms that regulate its activity remain unclear. Our study identifies U1C, a U1 snRNP-specific protein, as a key regulator of the SMN complex. U1C together with U1-70K facilitates U1 snRNP formation, rendering the SMN complex accessible for other snRNAs to assemble Sm cores. Remarkably, a prevalent cancer-associated mutation in U1 snRNA near the U1C binding site not only disrupts Sm core assembly but also sequesters the SMN complex, inhibiting canonical snRNP formation. Our findings provide mechanistic insights into how snRNP-specific proteins regulate the SMN complex and suggest that U1 snRNA mutations in numerous cancers disrupt the SMN complex, leading to perturbation in various RNA metabolism pathways. HighlightsO_LIU1C facilitates the formation of Sm core not only on U1 snRNA but also on other snRNAs. C_LIO_LIU1C together with U1-70K promotes U1 snRNP formation, enabling the SMN complex to recruit Gemin5/other snRNAs complex. C_LIO_LIThe divalent binding of U1C to the SMN complex is mediated by U1Cs N-terminus helix, interacting with U1-70K, and its arginine-methylated C-terminus domain, binding to the SMN protein. C_LIO_LIMultiple U1 snRNA mutations in cancer patients defect in Sm core assembly and potentially sequester the SMN complex, thereby inhibiting canonical snRNP formation. C_LI

biochemistry↗

bioRxiv2024

Cargo-selective regulation of clathrin-mediated endocytosis by AMP-activated protein kinase

The cell surface abundance of many proteins is controlled by clathrin-mediated endocytosis (CME). CME is driven by the assembly of clathrin and other proteins on the inner leaflet of the plasma membrane into clathrin-coated pits (CCPs). Regulation of CCP dynamics allows for control of the function of specific cell surface proteins, impacting a range of cellular outcomes. AMP-activated protein kinase (AMPK) becomes activated upon metabolic insufficiency and facilitates cellular adaptation to nutrient stress. Here, we examined how AMPK regulates CME and the cell surface membrane traffic of {beta}1-integrin. We find that AMPK controls CCP dynamics and regulates the abundance of the endocytic adaptor protein Dab2 within CCPs in a manner that requires the GTPase Arf6, thus selectively promoting the CCP recruitment and internalization of {beta}1-integrin. This reveals a novel signaling pathway for cargo-selective metabolic regulation of CME by AMPK, impacting the function of cell surface proteins such as integrins.

cell biology↗

bioRxiv2024

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimers disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

neuroscience↗

bioRxiv2024

Connectome predictive modeling of trait mindfulness

IntroductionTrait mindfulness refers to ones disposition or tendency to pay attention to their experiences in the present moment, in a non-judgmental and accepting way. Trait mindfulness has been robustly associated with positive mental health outcomes, but its neural underpinnings are poorly understood. Prior resting-state fMRI studies have associated trait mindfulness with within- and between-network connectivity of the default-mode (DMN), fronto-parietal (FPN), and salience networks. However, it is unclear how generalizable the findings are, how they relate to different components of trait mindfulness, and how other networks and brain areas may be involved. MethodsTo address these gaps, we conducted the largest resting-state fMRI study of trait mindfulness to-date, consisting of a pre-registered connectome predictive modeling analysis in 367 adults across three samples collected at different sites. ResultsIn the model-training dataset, we did not find connections that predicted overall trait mindfulness, but we identified neural models of two mindfulness subscales, Acting with Awareness and Non-judging. Models included both positive networks (sets of pairwise connections that positively predicted mindfulness with increasing connectivity) and negative networks, which showed the inverse relationship. The Acting with Awareness and Non-judging positive network models showed distinct network representations involving FPN and DMN, respectively. The negative network models, which overlapped significantly across subscales, involved connections across the whole brain with prominent involvement of somatomotor, visual and DMN networks. Only the negative networks generalized to predict subscale scores out-of-sample, and not across both test datasets. Predictions from both models were also negatively correlated with predictions from a well-established mind-wandering connectome model. ConclusionsWe present preliminary neural evidence for a generalizable connectivity models of trait mindfulness based on specific affective and cognitive facets. However, the incomplete generalization of the models across all sites and scanners, limited stability of the models, as well as the substantial overlap between the models, underscores the difficulty of finding robust brain markers of mindfulness facets.

neuroscience↗

bioRxiv2024

MITOCHONDRIAL ANTIVIRAL PATHWAYS CONTROL ANTI-HIV RESPONSES AND ISCHEMIC STROKE OUTCOMES VIA THE RIG-1 SIGNALING AND INNATE IMMUNITY MECHANISMS

Occludin (ocln) is one of the main regulatory cells of the blood-brain barrier (BBB). Ocln silencing resulted in alterations of the gene expression signatures of a variety of genes of the innate immunity system, including IFN-stimulated genes (ISGs) and the antiviral retinoic acid-inducible gene-1 (RIG-1) signaling pathway, which functions as a regulator of the cytoplasmic sensors upstream of the mitochondrial antiviral signaling protein (MAVS). Indeed, we observed dysfunctional mitochondrial bioenergetics, dynamics, and autophagy in our system. Alterations of mitochondrial bioenergetics and innate immune protection translated into worsened ischemic stroke outcomes in EcoHIV-infected ocln deficient mice. Overall, these results allow for a better understanding of the molecular mechanisms of viral infection in the brain and describe a previously unrecognized role of ocln as a key factor in the control of innate immune responses and mitochondrial dynamics, which affect cerebral vascular diseases such as ischemic stroke.

neuroscience↗

bioRxiv2024

Sex-focused analyses of M83 A53T hemizygous mouse model with recombinant human alpha-synuclein preformed fibril injection identifies female resilience to disease progression: A combined magnetic resonance imaging and behavioural study.

Alpha-synuclein (aSyn) pathology has been extensively studied in mouse models harbouring human mutations. In spite of the known sex differences in age of onset, prevalence and disease presentation in human synucleinopathies, the impact of sex on aSyn propagation has received very little attention. To address this need, we examined sex differences in whole brain signatures of neurodegeneration due to aSyn toxicity in the M83 mouse model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 m3 isotropic voxel; acquired -7, 30, 90 and 120 days post-injection [dpi]; n[≥]8 mice/group/sex/time point). To initiate aSyn spreading, M83 mice were inoculated with recombinant human aSyn preformed fibrils (Hu-PFF) or phosphate buffered saline (PBS) injected in the right dorsal striatum. We observed more aggressive neurodegenerative profiles over time for male M83 Hu-PFF-injected mice when examining voxel-wise trajectories. However, at 90 dpi, we observed widespread patterns of neurodegeneration in the female Hu-PFF-injected mice. These differences were not accompanied with any differences in motor symptom onset between the male and female Hu-PFF-injected mice. However, male Hu-PFF-injected mice reached their humane endpoint sooner. These findings suggest that post-motor symptom onset, even though more accelerated disease trajectories were observed for male Hu-PFF-injected mice, neurodegeneration may appear sooner in female Hu-PFF-injected mice (prior to motor symptomatology). These findings suggest that sex-specific synucleinopathy phenotypes urgently need to be considered to improve our understanding of neuroprotective and neurodegenerative mechanisms.

neuroscience↗

bioRxiv2024

A Near Infrared Fluorescent Nanosensor for Spatial and Dynamic Measurements of Auxin, Indole-3-Acetic Acid, in Planta

Auxins, particularly indole-3-acetic acid (IAA), is a phytohormone critical for plant growth, development, and response to environmental stimuli. Despite its importance, there is a lack of species-independent sensors that allow direct and reversible detection of IAA. Herein, we introduce a novel near infrared fluorescent nanosensor for spatial and temporal measurement of IAA in planta using Corona Phase Molecular Recognition. The IAA nanosensor shows high specificity to IAA in vitro and was validated to localize and function in plant cells. The sensor works across different plant species without optimization and allows visualization of dynamic changes to IAA distribution and movement in leaf tissues. The results highlighted the utility of IAA nanosensor for understanding IAA dynamics in planta.

bioengineering↗

bioRxiv2024

de Novo Sequencing of Antibodies for Identification of Neutralizing Antibodies in Human Plasma Post SARS-CoV-2 Vaccination

We present a method for sequencing polyclonal IgG enriched from human plasma, employing a combination of de novo sequencing, proteomics, bioinformatics, protein separation, sequencing, and peptide separations. Our study analyzes a single patients IgG antibody response triggered by the Moderna Spikevax mRNA COVID-19 vaccine. From the sequencing data of the natural polyclonal response to vaccination, we generated 12 recombinant antibodies. Six derived recombinant antibodies, including four generated with de novo sequencing, exhibited similar or higher binding affinities than the original natural polyclonal antibody. Our neutralization tests revealed that the six antibodies possess neutralizing capabilities against the target antigen. This research provides insights into sequencing polyclonal IgG antibodies while highlighting the effectiveness and potential of our approach in generating recombinant antibodies with robust binding affinity and neutralization capabilities. Our proposed approach is an advancement in characterizing the IgG response by directly investigating the circulating pool of IgG without relying exclusively on the B-cell repertoire or population. This is crucial as the B-cell analysis may not accurately represent the circulating antibodies. Interestingly, a large proportion (80 to 90%) of the human antibody sequences generated against SARS-CoV-2 in the literature have been derived solely from B-cell analysis. Therefore, the ability to offer a different perspective is crucial in gaining a comprehensive understanding of the IgG response. Significance StatementWe investigate human IgG targeting the receptor binding domain using de novo proteomics. The peripheral B-cell repertoire may not adequately cover all the circulating IgG for human IgG sequencing. Our approach overcomes this limitation by using a de novo protein sequencing on top of standard proteomics. We obtained distinct de novo sequences, showcasing our methods potential. The recombinant proteins we generate possess traits comparable to or surpassing the naturally occurring polyclonal antibodies (pAbs). This study highlights similarities and differences between IgG populations in blood and circulating B-cells, which is crucial for future biologics development.

immunology↗

bioRxiv2024

Forest and Biodiversity 2: a tree diversity experiment to understand the consequences of multiple dimensions of diversity and composition for long-term ecosystem function and resilience

O_LIWe introduce a new "low-density" tree diversity experiment at the Cedar Creek Ecosystem Science Reserve in central Minnesota, USA aimed at testing long-term ecosystem consequences of tree diversity and composition. The experiment was designed to provide guidance on forest restoration efforts that will simultaneously advance carbon sequestration goals and contribute to biodiversity conservation and sustainability. C_LIO_LIThe new Forest and Biodiversity (FAB2) experiment uses native tree species in varying levels of species richness, phylogenetic diversity, and functional diversity to test the mechanisms and processes that contribute to forest stability and ecosystem productivity in the face of global change. FAB2 was designed and established in conjunction with a prior experiment (FAB1) in which the same set of twelve species was planted in 16 m2 plots at high density (0.5 m spacing). In addition to lower density plantings (1 m spacing), FAB2 also has larger plots (100 m2 and 400 m2) appropriate for testing long-term ecosystem consequences of species composition and diversity. C_LIO_LIWithin the first six years, mortality in the 400 m2 monoculture plots was significantly higher than in the 100 m2 plots. The highest mortality among any treatments occurred in Tilia americana and Acer negundo monocultures, but mortality for both species decreased with increasing plot diversity. These results highlight the importance of forest diversity in reducing mortality in some species and point to potential mechanisms, including light and drought stress, that cause tree mortality in vulnerable monocultures. The experiment highlights challenges to maintaining monoculture and low-diversity treatments in tree mixture experiments of large extent. C_LIO_LIThe FAB2 experiment provides a long-term platform for discerning the importance of species and lineage effects and of multiple dimensions of diversity in restoring ecosystem functions and services provided by forests. It also provides a platform for improving remote sensing approaches, including Uncrewed Aerial Vehicles (UAVs) equipped with LiDAR, multispectral, and hyperspectral sensors, to complement ground-based monitoring of forest function and diversity. We aim for the experiment to contribute to international efforts to monitor and manage forests in the face of global change. C_LI

ecology↗

bioRxiv2024

Circadian regulation of endoplasmic reticulum calcium response in mouse cultured astrocytes

The circadian clock, an internal time-keeping system orchestrates 24-hour rhythms in physiology and behavior by regulating rhythmic transcription in cells. Astrocytes, the most abundant glial cells, play crucial roles in central nervous system (CNS) functions, but the impact of the circadian clock on astrocyte functions remains largely unexplored. In this study, we identified 412 circadian rhythmic transcripts in cultured mouse cortical astrocytes through RNA sequencing. Gene Ontology analysis indicated that genes involved in Ca2+ homeostasis are under circadian control. Notably, Herpud1 (Herp) exhibited robust circadian rhythmicity at both mRNA and protein levels, a rhythm disrupted in astrocytes lacking the circadian transcription factor, BMAL1. HERP regulated endoplasmic reticulum (ER) Ca2+ release by modulating the degradation of inositol 1,4,5-trisphosphate receptors (ITPRs). ATP-stimulated ER Ca2+ release varied with the circadian phase, being more pronounced at subjective night phase, likely due to the rhythmic expression of ITPR2. Correspondingly, ATP-stimulated cytosolic Ca2+ increases were heightened at the subjective night phase. This rhythmic ER Ca2+ response led to circadian phase-dependent variations in the phosphorylation of Connexin 43 (Ser368) and gap junctional communication. Given the role of gap junction channel (GJC) in propagating Ca2+ signals, we suggest that this circadian regulation of ER Ca2+ responses could affect astrocytic modulation of synaptic activity according to the time of day. Overall, our study enhances the understanding of how the circadian clock influences astrocyte function in the CNS, shedding light on their potential role in daily variations of brain activity and health.

neuroscience↗

bioRxiv2024

Adaptive thermogenesis is mediated by GDF15 via the GFRAL neuronal axis in mice

Adaptive thermogenesis is a key homeostatic mechanism that primarily occurs in brown adipocytes and enables the maintenance of body temperature. Although this process involves coordinated responses in multiple tissues, including the browning of white adipocytes, the precise inter-organ crosstalk underlying adaptive thermogenesis is unclear. Here, we investigate the pivotal role of the GDNF family receptor alpha-like (GFRAL) neuronal axis in modulating compensatory thermogenic responses in brown and white adipose depots under stress conditions, specifically the mitochondrial unfolded protein response resulting from genetic modification and cold exposure. We employed a mouse model with targeted deletion of Crif1 in the mitoribosomes of brown adipocytes, and cold-exposed mice and immortalized adipocytes, to uncover the mechanism by which mitochondrial stress-induced growth differentiation factor 15 (GDF15) expression affects metabolism and facilitates adaptive thermogenesis. We found that Crif1 deletion resulted in browning of inguinal white adipose depots, increased energy expenditure, reduced food intake, and resistance to weight gain. Retrograde neuronal tracing established that GFRAL-positive neurons in the hindbrain and sympathetic preganglionic neurons in the spinal cord mediated the GDF15-associated browning of inguinal white adipose tissue. Intervention studies using antisense oligonucleotides to inhibit Gfral expression blunted the effect of Crif1 deletion on energy expenditure and food intake, further confirming the essential role the GFRAL axis plays in GDF15-driven thermogenic adaptation in white adipose tissue. Our findings suggest that the GFRAL neuronal axis is key in coordinating the adaptive thermogenic response across multiple tissues and adipose depots, thereby ensuring metabolic homeostasis during mitochondrial stress.

molecular biology↗

bioRxiv2024

Hidden route of protein damage through confined oxygen gas

Oxidative modifications can severely impair protein structure, fold, and function, closely linked to human aging and diseases. Conventional oxidation pathways typically involve the free diffusion of reactive oxygen species (ROS), followed by chemical attacks on the protein surface. Here, we report a hidden route of protein oxidative damage, which we refer to as O2-confinement oxidation pathway. This pathway starts with the initial trapping of dissolved molecular oxygen (O2) within protein cavity spaces, followed by interaction with photosensitizing tryptophan residues. The trapped O2 is then converted to singlet oxygen (1O2), a powerful ROS, through spin-flip electron transfer mechanism under blue light. The generated 1O2 within the protein ultimately attacks the protein core residues through constrained diffusion, accelerating the oxidative damage. This alternative photooxidation pathway through the initial O2 trapping would bypass the antioxidant defense systems which target freely-diffusing ROS, constituting an additional layer of protein oxidative damage in cells and tissues.

biochemistry↗

bioRxiv2023

ADPKD-Causing Missense Variants in Polycystin-1 Disrupt Cell Surface Localization or Polycystin Channel Function

Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of this monogenic disorder, our limited mechanistic understanding of ADPKD has hindered therapeutic development. Here, we successfully developed bioassays that functionally classify missense variants in polycystin-1 (PC1). Strikingly, ADPKD pathogenic missense variants cluster into two major categories: 1) those that disrupt polycystin cell surface localization or 2) those that attenuate polycystin ion channel activity. We found that polycystin channels with defective surface localization could be rescued with a small molecule. We propose that small-molecule-based strategies to improve polycystin cell surface localization and channel function will be effective therapies for ADPKD patients.

cell biology↗

bioRxiv2023

Live Malassezia strains isolated from the mucosa of patients with ulcerative colitis

The human gut is inhabited by a complex ecosystem of diverse microorganisms. While most studies on the gut microbiota have focused on bacteria, accumulating evidence has underscored the role of the mycobiota in inflammatory bowel disease (IBD). This study is the first to isolate and characterize live Malassezia globosa strains from the intestinal mucosa of patients with ulcerative colitis. Malassezia species primarily inhabit the human skin. We therefore compared the M. globosa gut isolates with the M. globosa skin isolates and noted a striking disparity between them. The gut isolates led to a greater exacerbation of colitis in mice. Transcriptome analysis revealed that the gut isolates were more sensitive to normoxia than the skin isolates, suggesting adaptation to hypoxia prevalent in the intestinal environment. These findings provide novel insights into the potential impact of M. globosa on the pathogenesis of IBD and the influence of niche-specific adaptations on its virulence.

microbiology↗

bioRxiv2023

Cellular RNA interacts with MAVS to promote antiviral signaling

Immune signaling needs to be well-regulated to promote clearance of pathogens, while preventing aberrant inflammation. Interferons (IFNs) and antiviral genes are activated by the detection of viral RNA by RIG-I-like receptors (RLRs). Signal transduction downstream of RLRs proceeds through a multi-protein complex organized around the central adaptor protein MAVS. Recent work has shown that protein complex function can be modulated by RNA molecules providing allosteric regulation or acting as molecular guides or scaffolds. Thus, we hypothesized that RNA plays a role in organizing MAVS signaling platforms. Here, we show that MAVS, through its central intrinsically disordered domain, directly interacts with the 3' untranslated regions of cellular mRNAs. Importantly, elimination of RNA by RNase treatment disrupts the MAVS signalosome, including newly identified regulators of RLR signaling, and inhibits phosphorylation of the transcription factor IRF3. This supports the hypothesis that RNA molecules scaffold proteins in the MAVS signalosome to induce IFNs. Together, this work uncovers a function for cellular RNA in promoting signaling through MAVS and highlights a generalizable principle of RNA regulatory control of cytoplasmic immune signaling complexes.

immunology↗

bioRxiv2023

Sulfasalazine promotes myogenic differentiation via increasing of fast myosin heavy chain isoforms

Sarcopenia is a debilitating condition characterized by the progressive and generalized degeneration of skeletal muscle mass and function. As of now, there is no approved pharmacological treatment for sarcopenia. Previously, our research revealed that Yin Yang 1 (YY1) plays a crucial role in PHD finger protein 20 (PHF20)-mediated myogenic differentiation. A significant enhancement in YY1 transcription, mediated by PHF20, was observed in C2C12 myoblasts. Within skeletal muscle, YY1 is traditionally considered to inhibit myogenesis by directly repressing the synthesis of late-stage differentiation genes, such as skeletal muscle actin, muscle creatine kinase, and myosin heavy chain IIb. Through screening of a drug library using a PHF20/YY1 promoter reporter assay, sulfasalazine emerged as a promising candidate. Sulfasalazine is known for its anti-inflammatory and immunomodulatory properties and is commonly prescribed for autoimmune diseases. In this study, the treatment of C2C12 myoblasts with sulfasalazine accelerated the myogenic differentiation and bolstered the gene and protein expression of fast myosin heavy chain via a metabolic shift towards glycolysis. Additionally, oral administration of sulfasalazine demonstrated improvement in physical performance in aged mice, as well as in mice models with hindlimb disuse or damage. Moreover, sulfasalazine exhibited a remarkable ability to facilitate the recovery of muscle fibers damaged by Velcro immobilization. Collectively, our findings suggest that sulfasalazine could represent a novel therapeutic avenue for the amelioration of muscle weakness, including sarcopenia.

biochemistry↗

bioRxiv2023

Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation

Halting breast cancer metastatic relapses following primary tumor removal and the clinical dormant phase, remains challenging, due to a lack of specific vulnerabilities to target during dormancy. To address this, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). We discovered that loss of class-III PI3K, Pik3c3, revealed a unique vulnerability in 4T07 cells. Surprisingly, dormancy-prone 4T07 cells exhibited higher mTORC1 activity than 4T1 cells, due to lysosome-dependent signaling occurring at the cell periphery. Pharmacological inhibition of Pik3c3 counteracted this phenotype in 4T07 cells, and selectively reduced metastasis burden only in the 4T07 dormancy-prone model. This mechanism was also detected in human breast cancer cell lines in addition to a breast cancer patient-derived xenograft supporting that it may be relevant in humans. Our findings suggest dormant cancer cell-initiated metastasis may be prevented in patients carrying tumor cells that display PIK3C3-peripheral lysosomal signaling to mTORC1. Statement of SignificanceWe reveal that dormancy-prone breast cancer cells depend on the class III PI3K to mediate a constant peripheral lysosomal positioning and mTORC1 hyperactivity. Targeting this pathway might blunt breast cancer metastasis.

cancer biology↗