Biology subjects

Zhou, W.

Publications and source records attributed to Zhou, W..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

Renal fibrosis is a common pathological endpoint in chronic kidney disease (CKD) that is challenging to reverse. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM) in fibrotic kidney, recent studies have unveiled their diversity in terms of proliferative and fibrotic characteristics. This diversity could be linked with the existence of different metabolic states, and myofibroblast metabolic reprogramming may contribute to the pathogenesis and progression of renal fibrosis. Here, we reveal an unexpected role of the E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of myofibroblasts during renal fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients, and in pre-clinical murine models of CKD. WWP2 deficiency increases fatty acid oxidation and activates the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. This concurrently promotes myofibroblast proliferation and halts pro-fibrotic activation, reducing the severity of kidney fibrosis. Mechanistically, WWP2 suppresses the transcription of PGC-1, a metabolic mediator shaping myofibroblast fibrotic response. Pharmacological interventions targeting PGC-1 reverse the effects of WWP2 on fibrotic myofibroblasts. These findings demonstrate the influence of WWP2 on essential metabolic pathways involved in fibrogenesis, uncovering the WWP2-PGC-1 axis that orchestrates the metabolic reprogramming of myofibroblasts during renal fibrosis. Our study presents a potential novel target for therapeutic intervention in the treatment of chronic kidney disease. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/554242v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1847ffeorg.highwire.dtl.DTLVardef@1ef029aorg.highwire.dtl.DTLVardef@93e0f1org.highwire.dtl.DTLVardef@950d49_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWWP2 expression is elevated in the tubulointerstitium of fibrotic kidneys and contributes to CKD pathogenesis and progression. C_LIO_LIWWP2 uncouples the pro-fibrotic activation and cell proliferation in renal myofibroblasts. C_LIO_LIWWP2 controls mitochondrial respiration in renal myofibroblasts through the metabolic regulator PGC-1 C_LIO_LIMyofibroblast metabolic reprogramming mediates the effect of WWP2 on fibrotic myofibroblasts. C_LI

cell biology↗

bioRxiv2023

A pro-inflammatory stem cell niche drives myelofibrosis through a targetable galectin 1 axis

Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. The majority of patients present with early-stage disease, but a substantial proportion progress to myelofibrosis and/or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and we lack therapies that reliably prevent or reverse fibrosis development. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the crosstalk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a quartet of immune and stromal cell lineages - with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells and pro-inflammatory fibroblasts. We identified the y-galactoside binding protein galectin 1 as a striking biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts, and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival following galectin 1 inhibition. In human bone marrow organoids, TNF increased galectin 1 expression, suggesting a feedback loop wherein the pro-inflammatory MPN clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a valuable resource for studying hematopoietic cell-niche interactions, with broad relevance for cancer-associated inflammation and disorders of tissue fibrosis.

cancer biology↗

bioRxiv2023

Tremors in Time: Mechanically Induced Motor Tremors Influence

Contemporary research has begun to show a strong relationship between movements and the perception of time. More specifically, concurrent movements serve to both bias and enhance time estimates. To explain these effects, we recently proposed a mechanism by which movements provide a secondary channel for estimating duration that is combined optimally with sensory estimates, in accordance with Bayesian cue combination. However, a critical test of this framework is that by introducing "noise" into movements, sensory estimates of time should similarly become noisier in a manner predicted by cue combination equations. To accomplish this, we had human participants move a robotic arm while estimating intervals of time in either auditory or visual modalities (n=24, ea.). Crucially, we introduced an artificial "tremor" in the arm while subjects were moving, that varied across three levels of amplitude (1-3 N) or frequency (4-12 Hz). The results of both experiments revealed that increasing the frequency of the tremor led to noisier estimates of duration, but in such a way that higher levels of noise saturated the impact, consistent with optimal integration. Further, the effect of noise varied with the base precision of the interval, such that a naturally less precise timing (i.e. visual) was more influenced by the tremor than a naturally more precise modality (i.e. auditory). To explain these findings, we fit the data with a recently developed drift-diffusion model of perceptual decision making, in which the momentary, within-trial variance was allowed to vary across conditions. Here, we found that the model could recapitulate the observed findings, further supporting the theory that movements influence perception directly. Overall, our findings support the proposed framework, and demonstrate the utility of inducing motor noise via artificial tremors, thus providing clinical utility in their connection to movement disorders characterized by tremors.

neuroscience↗

bioRxiv2023

Astrocytes gate long-term potentiation in hippocampal interneurons

Long-term potentiation is involved in physiological processes such as learning and memory, motor learning and sensory processing, and pathological conditions such as addiction. In contrast to the extensive studies on the mechanism of long-term potentiation on excitatory glutamatergic synapses onto excitatory neurons (LTPE[->]E), the mechanism of LTP on excitatory glutamatergic synapses onto inhibitory neurons (LTPE[->]I) remains largely unknown. In the central nervous system, astrocytes play an important role in regulating synaptic activity and participate in the process of LTPE[->]E, but their functions in LTPE[->]I remain incompletely defined., We studied the role of astrocytes in regulating LTPE[->]I in the hippocampal CA1 region and their impact on cognitive function using electrophysiological, pharmacological, confocal calcium imaging, chemogenetics and behavior tests. We showed that LTPE[->]I in the stratum oriens of hippocampal CA1 is astrocyte independent. However, in the stratum radiatum, synaptically released endocannabinoids increase astrocyte Ca2+ via type-1 cannabinoid receptors, stimulate D-serine release, and potentiate excitatory synaptic transmission on inhibitory neurons through the activation of (N-methyl-D-aspartate) NMDA receptors. We also revealed that chemogenetic activation of astrocytes is sufficient for inducing NMDA-dependent de novo LTPE[->]I in the stratum radiatum of the hippocampus. Furthermore, we found that disrupting LTPE[->]I by knocking down {gamma}CaMKII in interneurons of the stratum radiatum resulted in dramatic memory impairment. Our findings suggest that astrocytes release D-serine, which activates NMDA receptors to regulate LTPE[->]I, and that cognitive function is intricately linked with the proper functioning of this LTPE[->]I pathway.

neuroscience↗

bioRxiv2023

Positive selection and relaxed purifying selection contribute to rapid evolution of male-biased genes in a dioecious flowering plant

Sex-biased genes offer insights into the evolution of sexual dimorphism. Sex-biased genes, especially those with male bias, show elevated evolutionary rates of protein sequences driven by positive selection and relaxed purifying selection in animals. Although rapid sequence evolution of sex-biased genes and evolutionary forces have been investigated in animals and brown algae, less is known about evolutionary forces in dioecious angiosperms. In this study, we separately compared the expression of sex-biased genes between female and male floral buds and between female and male flowers at anthesis in dioecious Trichosanthes pilosa (Cucurbitaceae). In floral buds, sex-biased gene expression was pervasive, and had significantly different roles in sexual dimorphism such as physiology. We observed higher rates of sequence evolution for male-biased genes in floral buds compared to female-biased and unbiased genes. Male-biased genes under positive selection were mainly associated with functions to abiotic stress and immune responses, suggesting that high evolutionary rates are driven by adaptive evolution. Additionally, relaxed purifying selection may contribute to accelerated evolution in male-biased genes generated by gene duplication. Our findings, for the first time in angiosperms, suggest evident rapid evolution of male-biased genes, advance our understanding of the patterns and forces driving the evolution of sexual dimorphism in dioecious plants.

evolutionary biology↗

bioRxiv2023

Insights from the Early Cretaceous: The promise of Lycoptera aDNA sequencing

Obtaining high-quality ancient DNA (aDNA) is a crucial process for advancements in molecular paleontology. However, current research is restricted to a limited range of fossil types due to DNA degradation and contamination from environmental DNA (eDNA). Utilizing the technology of nanoparticle affinity beads, we successfully extracted DNA from Lycoptera davidi fossils and obtained 1,258,901 DNA sequences. To ascertain their origins, we developed and implemented a novel protocol, the "mega screen method", designed to categorize aDNA fragments. This approach successfully identified 243 Actinopterygii species-specific fragments (SSFs), which subsequent analysis confirmed as original in situ DNA (oriDNA) sequences. Lycoptera davidi, a ray-finned fish from the Early Cretaceous Jehol Biota, dates back approximately 120 million years (Ma). Notably, the absence of deamination in certain oriDNA and paleoenvironmental DNA (paeDNA) fragments calls into question its reliability as a definitive marker for aDNA identification, a phenomenon potentially attributable to the protective effects of fossil diagenesis. Additionally, we identified a novel mechanism, "coding region sliding replication and recombination", responsible for generating new transposase. This mechanism, distinct from conventional processes such as horizontal gene transfer or vertical inheritance from parents, can facilitate a rapid genomic diversification. The transposase CDS insertion into the GAS2 gene of Anabarilius grahami offers molecular insights into the genetic interactions between ancestral carp and Lycoptera and the swift emergence of the expansion of early fish species starting from the early Cretaceous. These findings enhance our understanding of fossil DNA preservation, lay the groundwork for an ancient species DNA database, and introduce innovative tools for exploring evolutionary relationships across geological timescales.

paleontology↗

bioRxiv2023

Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the gas and breaks to finely tune iron-regulated tumor progression.

cancer biology↗

bioRxiv2023

EphrinB2 knockdown in spinal cord astrocytes preserves diaphragm innervation in a mutant SOD1 mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 in the cervical spinal cord ventral horn via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism in mutant SOD1-associated ALS and a promising therapeutic target.

neuroscience↗

bioRxiv2023

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

cancer biology↗

bioRxiv2023

Using macromolecular electron densities to improve the enrichment of active compounds in virtual screening

The quest for more effective virtual screening algorithms is hindered by the scarcity of training data, calling for innovative approaches. This study presents the first use of experimental electron density (ED) data for improving active compound enrichment in virtual screening, supported by EDs ability to reflect the time-averaged behavior of ligands and solvents in the binding pocket. Experimental ED-based grid matching score (ExptGMS) was developed to score compounds by measuring the degree of matching between their binding conformations and a series of multi-resolution experimental ED grids. The efficiency of ExptGMS was validated using both in-silico tests with the Directory of Useful Decoys-Enhanced dataset and wet-lab tests on Covid-19 3CLpro-inhibitors. ExptGMS improved the active compound enrichment in top-ranked molecules by approximately 20%. Furthermore, ExptGMS helped identify four new and active inhibitors of 3CLpro, with the top showing an IC50 value of 1.9 {micro}M. To facilitate the use of ExptGMS, we developed an online database containing experimental ED grids for over 17,000 proteins.

bioinformatics↗

bioRxiv2023

Deciphering the gut microbiome of grass carp through multi-omics approach

BackgroundAquaculture plays an important role in global protein supplies and food security. The ban on antibiotics as feed additive proposes urgent need to develop alternatives. Gut microbiota plays important roles in the metabolism and immunity of fish, and has the potential to give rise to novel green inputs for fish culture. However, our understanding of fish gut microbiome is still lacking. ResultsWe identified 575,856 non-redundant genes by metagenomic sequencing of the intestinal content samples of grass carp. Taxonomic and functional annotation of the gene catalogue revealed specificity of the gut microbiome of grass carp compared with mammals. Co-occurrence analysis indicated exclusive relations between the genera belonging to Proteobacteria and Fusobacteria/Firmicutes/Bacteroidetes, suggesting two independent ecological groups of the microbiota. The association pattern of Proteobacteria with the gene expression modules of fish gut and liver was consistently opposite to that of Fusobacteria, Firmicutes and Bacteroidetes, implying differential functionality of Proteobacteria and Fusobacteria/Firmicutes/Bacteroidetes. Therefore, the two ecological groups were divided into two functional groups, i.e., Functional Group 1: Proteobacteria; Functional Group 2: Fusobacteria/Firmicutes/Bacteroidetes. Further analysis revealed that the two functional groups differ in genetic capacity for carbohydrate utilization, virulence factors and antibiotic resistance. Finally, we proposed that the ratio of "Functional Group 2/Functional Group 1" can be used as a biomarker that efficiently reflects the structural and functional characteristics of the microbiota of grass carp. ConclusionsThe gene catalogue is an important resource for investigating the gut microbiome of grass carp. Multi-omics analysis provides insights into functional implications of the main phyla that comprise the fish microbiota, and shed lights on targets for microbiota regulation.

microbiology↗

bioRxiv2023

Coordinated transformation of object representations across human visual cortex

Our brain constructs increasingly sophisticated representations along the ventral visual pathway to support object recognition. To understand how these representations unfold over time, we recorded human intracranial electroencephalography responses to 120 object images at five consecutive stages of the ventral pathway from V1 to occipitotemporal areas. Using representational similarity analysis, we confirmed that response patterns were more strongly driven by low-order stimulus properties at early stages and high-order category information at late stages, respectively. Interestingly, response patterns also became less stimulus-driven and more categorical at all stages over time, from [~]100 to 200 ms post-stimulus. During this period, we found significant noise correlation between single-trial response patterns across stages, indicating tight inter-areal coupling. Thus, multi-areal recurrent processes may be essential in building high-order object representations.

neuroscience↗

bioRxiv2023

NeoTCR: an immunoinformatic database of experimentally-supported functional neoantigen-specific TCR sequences

Neoantigen-based immunotherapy has demonstrated of long-lasting antitumor activity. Recognition of neoantigens by T cell receptors (TCRs) is considered a trigger for antitumor responses. Due to the overwhelming number of TCR repertoires in the human genome, it is challenging to computationally pinpoint neoantigen-specific TCRs. Recent studies have identified a number of functional neoantigen-specific TCRs, but the corresponding information is scattered across published literature and is difficult to retrieve. To improve access to these data, we developed the NeoTCR, an immunoinformatic database containing a unified description of publicly available neoantigen-specific TCR sequences, as well as relevant information on targeted neoantigens, from experimentally supported studies across 18 cancer subtypes. A user-friendly web interface allows interactive browsing and running of complex database queries based on numerous criteria. To facilitate rapid identification of neoantigen-specific TCRs from raw sequencing data, NeoTCR offers a one-stop analysis for annotation and visualization of TCR clonotypes, discovery of existing neoantigen-specific TCRs, and exclusion of bystander viral-associated TCRs. NeoTCR will serve as a valuable platform to study the biological functions of neoantigen-associated T-cells in anti-tumor immunity to better apply neoantigen-specific TCRs in clinics. NeoTCR is available at http://www.neotcrdb.com/.

bioinformatics↗

bioRxiv2023

BAF chromatin complexes do not mediate GLI transcriptional repression of Hedgehog target genes

Transcriptional responses to the Hedgehog (HH) signaling pathway are primarily modulated by GLI repression in the mouse limb. Previous studies suggested a role for the BAF chromatin remodeling complex in mediating GLI repression. Consistent with this possibility, the core BAF complex protein SMARCC1 is present at most active limb enhancers including the majority of GLI enhancers. However, in contrast to GLI repression which reduces chromatin accessibility, SMARCC1 maintains chromatin accessibility at most enhancers, including those bound by GLI. Moreover, SMARCC1 binding at GLI-regulated enhancers occurs independently of GLI3. Consistent with previous studies, some individual GLI target genes are mis-regulated in Smarcc1 conditional knockouts, though most GLI target genes are unaffected. Moreover, SMARCC1 is not necessary for mediating constitutive GLI repression in HH mutant limb buds. We conclude that SMARCC1 does not mediate GLI3 repression, which we propose utilizes alternative chromatin remodeling complexes.

developmental biology↗

bioRxiv2023

Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate in aging fibroblasts

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species 1-3 and recently demonstrated to occur in rare instances from one human generation to the next 4. Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals. Compared to circulating immune cells (n=389), post-mitotic brain tissue (n=798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. Second, we tested the dynamic transfer of Numts using a repeated-measures WGS design in a human fibroblast model that recapitulates several molecular hallmarks of aging 5. These longitudinal experiments revealed a gradual accumulation of one Numt every [~]13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7- fold faster than healthy donors. Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human post-mitotic tissues produce functionally-relevant human Numts over timescales shorter than previously assumed.

genomics↗

bioRxiv2023

Skin microbiome attributes associate with biophysical skin aging

Two major arms of skin aging are changes in the skins biophysical conditions and alterations in the skin microbiome. This work partitioned both arms to study their interaction in detail. Leveraging the resolution provided by shotgun metagenomics, we explored how skin microbial species, strains, and gene content interact with the biophysical traits of the skin during aging. With a dataset well-controlled for confounding factors, we found that skin biophysical traits, especially the collagen diffusion coefficient, are associated with the composition and the functional potential of the skin microbiome, including the abundance of bacterial strains found in nosocomial infections and the abundance of antibiotic resistance genes. Our findings reveal important associations between skin biophysical features and aging-related changes in the skin microbiome and generate testable hypotheses for the mechanisms of such associations.

genomics↗

bioRxiv2023

PerturbSci-Kinetics: Dissecting key regulators of transcriptome kinetics through scalable single-cell RNA profiling of pooled CRISPR screens

Here we described PerturbSci-Kinetics, a novel combinatorial indexing method for capturing three-layer single-cell readout (i.e., whole transcriptomes, nascent transcriptomes, sgRNA identities) across hundreds of genetic perturbations. Through PerturbSci-Kinetics profiling of pooled CRISPR screens targeting a variety of biological processes, we were able to decipher the complexity of RNA regulations at multiple levels (e.g., synthesis, processing, degradation), and revealed key regulators involved in miRNA and mitochondrial RNA processing pathways. Our technique opens the possibility of systematically decoding the genome-wide regulatory network underlying RNA temporal dynamics at scale and cost-effectively.

genomics↗

bioRxiv2023

Loss of the endocytic tumor suppressor HD-PTP phenocopies LKB1 and promotes RAS-driven oncogenesis.

Abstract/SummaryOncogenic RAS mutations drive aggressive cancers that are difficult to treat in the clinic, and while direct inhibition of the most common KRAS variant in lung adenocarcinoma (G12C) is undergoing clinical evaluation, a wide spectrum of oncogenic RAS variants together make up a large percentage of untargetable lung and GI cancers. Here we report that loss-of-function alterations (mutations and deep deletions) in the gene that encodes HD-PTP (PTPN23) occur in up to 14% of lung cancers in the ORIEN Avatar lung cancer cohort, associate with adenosquamous histology, and occur alongside an altered spectrum of KRAS alleles. Furthermore, we show that in publicly available early-stage NSCLC studies loss of HD-PTP is mutually exclusive with loss of LKB1, which suggests they restrict a common oncogenic pathway in early lung tumorigenesis. In support of this, knockdown of HD-PTP in RAS-transformed lung cancer cells is sufficient to promote FAK-dependent invasion. Lastly, knockdown of the Drosophila homolog of HD-PTP (dHD-PTP/Myopic) synergizes to promote RAS-dependent neoplastic progression. Our findings highlight a novel tumor suppressor that can restrict RAS-driven lung cancer oncogenesis and identify a targetable pathway for personalized therapeutic approaches for adenosquamous lung cancer.

cancer biology↗