Hyperglycemia, or elevated blood glucose, renders individuals more prone to developing severe Staphylococcus aureus infections. S. aureus is the most common etiological agent of musculoskeletal infection, which is a common manifestation of disease in hyperglycemic patients. However, the mechanisms by which S. aureus causes severe musculoskeletal infection during hyperglycemia are incompletely characterized. To examine the influence of hyperglycemia on S. aureus virulence during invasive infection, we used a murine model of osteomyelitis and induced hyperglycemia with streptozotocin. We discovered that hyperglycemic mice exhibited increased bacterial burdens in bone and enhanced dissemination compared to control mice. Furthermore, infected hyperglycemic mice sustained increased bone destruction relative to euglycemic controls, suggesting that hyperglycemia exacerbates infection-associated bone loss. To identify genes contributing to S. aureus pathogenesis during osteomyelitis in hyperglycemic animals relative to euglycemic controls, we used transposon sequencing (TnSeq). We identified 71 genes uniquely essential for S. aureus survival in osteomyelitis in hyperglycemic mice and another 61 mutants with compromised fitness. Among the genes essential for S. aureus survival in hyperglycemic mice was the gene encoding superoxide dismutase A (), one of two S. aureus superoxide dismutases involved in detoxifying reactive oxygen species (ROS). We determined that a mutant exhibits attenuated survival in high glucose and during osteomyelitis in hyperglycemic mice. SodA therefore plays an important role during growth in high glucose and promotes S. aureus survival in bone. Collectively, these studies demonstrate that hyperglycemia increases the severity of osteomyelitis and identify genes contributing to S. aureus survival during hyperglycemic infection. <<<

Pattern separation, or the process by which highly similar stimuli or experiences in memory are represented by non-overlapping neural ensembles, has typically been ascribed to processes supported by the hippocampus. Converging evidence from a wide range of studies, however, suggests that pattern separation is a multistage process supported by a network of brain regions. Based on this evidence, considered together with related findings from the interference resolution literature, we propose the 'cortico-hippocampal pattern separation' (CHiPS) framework, which asserts that brain regions involved in cognitive control play a significant role in pattern separation. Particularly, these regions may contribute to pattern separation by (1) resolving interference in sensory regions that project to the hippocampus, thus regulating its cortical input, or (2) directly modulating hippocampal processes in accordance with task demands. Considering recent interest in how hippocampal operations are modulated by goal states likely represented and regulated by extra-hippocampal regions, we argue that pattern separation is similarly supported by neocortical-hippocampal interactions. <<<

Hongxi Zhang, Jia Li, Xiaoli Su, Yang Hu, Tianmei Liu, Shaoqing Ni, Haifeng Li, Xi-Nian Zuo, Junfen Fu, Ti-Fei Yuan, Zhi Yang <<<

Brain development from 1 to 6 years of age anchors a wide range of functional capabilities and carries early signs of neurodevelopmental disorders. However, quantitative models for depicting brain morphology changes and making individualized inferences are lacking, preventing the identification of early brain atypicality during this period. With a sample size of 285, we characterized the age dependence of the cortical thickness and subcortical volume in neurologically normal children and constructed quantitative growth charts of all brain regions for preschool children. While the cortical thickness of most brain regions decreased with age, the entorhinal and parahippocampal regions displayed an inverted-U shape of age dependence. Compared to the cortical thickness, the normalized volume of subcortical regions exhibited more divergent trends, with some regions increasing, some decreasing, and some displaying inverted-U-shaped trends. The growth curve models for all brain regions demonstrated utilities in identifying brain atypicality. The percentile measures derived from the growth curves facilitate the identification of children with developmental speech and language disorders with an accuracy of 0.875 (area under the receiver operating characteristic curve: 0.943). Our results fill the knowledge gap in brain morphometrics in a critical development period and provide an avenue for individualized brain developmental status evaluation with demonstrated sensitivity. The brain growth charts are shared with the public (http://phi-group.top/resources.html). <<<

Keren Yizhak, François Aguet, Jaegil Kim, Julian M Hess, Kirsten Kübler, Jonna Grimsby, Ruslana Frazer, Hailei Zhang, Nicholas J Haradhvala, Daniel Rosebrock, Dimitri Livitz, Xiao Li, Eila Arich-Landkof, Noam Shoresh, Chip Stewart, Ayellet V Segrè, Philip A Branton, Paz Polak, Kristin G Ardlie, Gad Getz <<<

How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease. <<<

Maxime Meylan, Florent Petitprez, Etienne Becht, Antoine Bougoüin, Guilhem Pupier, Anne Calvez, Ilenia Giglioli, Virginie Verkarre, Guillaume Lacroix, Johanna Verneau, Chen-Ming Sun, Pierre Laurent-Puig, Yann-Alexandre Vano, Reza Elaïdi, Arnaud Méjean, Rafaël Sanchez-Salas, Eric Barret, Xavier Cathelineau, Stephane Oudard, Claude-Agnès Reynaud, Aurélien de Reyniès, Catherine Sautès-Fridman, Wolf Herman Fridman <<<

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects. <<<

Luxi Chen, Jing Li, Renqiang Yuan, Yujie Wang, Jiaman Zhang, Yu Lin, Lina Wang, Xingxing Zhu, Wei Zhu, Jingyi Bai, Fanli Kong, Bo Zeng, Lu Lu, Jideng Ma, Keren Long, Long Jin, Zhiqing Huang, Jinlong Huo, Yiren Gu, Danyang Wang, Delin Mo, Diyan Li, Qianzi Tang, Xuewei Li, Jiangwei Wu, Yaosheng Chen, Mingzhou Li <<<

Liver development is a complex process that is regulated by a series of signaling pathways. Three-dimensional (3D) chromatin architecture plays an important role in transcriptional regulation; nonetheless, its dynamics and role in the rapid transition of core liver functions during development and obesity-induced metabolic stress remain largely unexplored. To investigate the dynamic chromatin architecture during liver development and under metabolic stress, we generated high-resolution maps of chromatin architecture for porcine livers across six major developmental stages (from embryonic day 38 to the adult stage) and under a high-fat diet-induced obesity. The characteristically loose chromatin architecture supports a highly plastic genome organization during early liver development, which fundamentally contributes to the rapid functional transitions in the liver after birth. We reveal the multi-scale reorganization of chromatin architecture and its influence on transcriptional regulation of critical signaling processes during liver development, and show its close association with transition in hepatic functions (i.e., from hematopoiesis in the fetus to metabolism and immunity after birth). The limited changes in chromatin structure help explain the observed metabolic adaptation to excessive energy intake in pigs. These results provide a global overview of chromatin architecture dynamics associated with the transition of physiological liver functions between prenatal development and postnatal maturation, and a foundational resource that allows for future in-depth functional characterization. <<<

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication. <<<

Hydrothermal plumes transport reduced chemical species and metals into the open ocean. Despite their considerable spatial scale and impact on biogeochemical cycles, niche differentiation of abundant microbial clades is poorly understood. Here, we analyzed the microbial ecology of two bathy- (Brothers volcano; BrV-cone and northwest caldera; NWC) and a mesopelagic (Macauley volcano; McV) plumes on the Kermadec intra-oceanic arc in the South Pacific Ocean. The microbial community structure, determined by a combination of 16S rRNA gene, fluorescence in situ hybridization and metagenome analysis, was similar to the communities observed in other sulfur-rich plumes. This includes a dominance of the vent characteristic SUP05 clade (up to 22% in McV and 51% in BrV). In each of the three plumes analyzed, the community was dominated by a different yet uncultivated chemoautotrophic SUP05 species, here, provisionally named, Candidatus Thioglobus vadi (McV), Candidatus Thioglobus vulcanius (BrV-cone) and Candidatus Thioglobus plumae (BrV-NWC). Statistical analyses, genomic potential and mRNA expression profiles suggested a SUP05 niche partitioning based on sulfide and iron concentration as well as water depth. A fourth SUP05 species was present at low frequency throughout investigated plume samples and may be capable of heterotrophic or mixotrophic growth. Taken together, we propose that small variations in environmental parameters and depth drive SUP05 niche partitioning in hydrothermal plumes. <<<

Wen Zhang, Mengze Lyu, Nicholas J Bessman, Zili Xie, Mohammad Arifuzzaman, Hiroshi Yano, Christopher N Parkhurst, Coco Chu, Lei Zhou, Gregory G Putzel, Ting-Ting Li, Wen-Bing Jin, Jordan Zhou, JRI Live Cell Bank, Hongzhen Hu, Amy M Tsou, Chun-Jun Guo, David Artis <<<

Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1 nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with GramClostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1 nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis. <<<

The purpose of this study was to determine the deep sequencing and analytic conditions needed to detect fetal subchromosome abnormalities across the genome from a maternal blood sample. Cell-free (cf) DNA was isolated from the plasma of 11 pregnant women carrying fetuses with subchromosomal duplications and deletions, translocations, mosaicism, and trisomy 20 diagnosed by metaphase karyotype. Massively parallel sequencing (MPS) was performed with 25-mer tags at approximately 10(9) tags per sample and mapped to reference human genome assembly hg19. Tags were counted and normalized to fixed genome bin sizes of 1 Mb or 100 kb to detect statistically distinct copy-number changes compared to the reference. All seven cases of microdeletions, duplications, translocations, and the trisomy 20 were detected blindly by MPS, including a microdeletion as small as 300 kb. In two of these cases in which the metaphase karyotype showed additional material of unknown origin, MPS identified both the translocation breakpoint and the chromosomal origin of the additional material. In the four mosaic cases, the subchromosomal abnormality was not demonstrated by MPS. This work shows that in nonmosaic cases, it is possible to obtain a fetal molecular karyotype by MPS of maternal plasma cfDNA that is equivalent to a chromosome microarray and in some cases is better than a metaphase karyotype. This approach combines the advantage of enhanced fetal genomic resolution with the improved safety of a noninvasive maternal blood test. <<<

Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing. <<<

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide and its incidence continues to increase year by year. Endoplasmic reticulum stress (ERS) caused by protein misfolding within the secretory pathway in cells and has an extensive and deep impact on cancer cell progression and survival. Growing evidence suggests that the genes related to ERS are closely associated with the occurrence and progression of HCC. This study aimed to identify an ERS-related signature for the prospective evaluation of prognosis in HCC patients. RNA sequencing data and clinical data of patients from HCC patients were obtained from The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC). Using data from TCGA as a training cohort (n=424) and data from ICGC as an independent external testing cohort (n=243), ERS-related genes were extracted to identify three common pathways IRE1, PEKR, and ATF6 using the GSEA database. Through univariate and multivariate Cox regression analysis, 5 gene signals in the training cohort were found to be related to ERS and closely correlated with the prognosis in patients of HCC. A novel 5-gene signature (including HDGF, EIF2S1, SRPRB, PPP2R5B and DDX11) was created and had power as a prognostic biomarker. The prognosis of patients with high-risk HCC was worse than that of patients with low-risk HCC. Multivariate Cox regression analysis confirmed that the signature was an independent prognostic biomarker for HCC. The results were further validated in an independent external testing cohort (ICGC). Also, GSEA indicated a series of significantly enriched oncological signatures and different metabolic processes that may enable a better understanding of the potential molecular mechanism mediating the progression of HCC. The 5-gene biomarker has a high potential for clinical applications in the risk stratification and overall survival prediction of HCC patients. In addition, the abnormal expression of these genes may be affected by copy number variation, methylation variation, and post-transcriptional regulation. Together, this study indicated that the genes may have potential as prognostic biomarkers in HCC and may provide new evidence supporting targeted therapies in HCC. <<<

Learning a faithful directed acyclic graph (DAG) from samples of a joint distribution is a challenging combinatorial problem, owing to the intractable search space superexponential in the number of graph nodes. A recent breakthrough formulates the problem as a continuous optimization with a structural constraint that ensures acyclicity (Zheng et al., 2018). The authors apply the approach to the linear structural equation model (SEM) and the least-squares loss function that are statistically well justified but nevertheless limited. Motivated by the widespread success of deep learning that is capable of capturing complex nonlinear mappings, in this work we propose a deep generative model and apply a variant of the structural constraint to learn the DAG. At the heart of the generative model is a variational autoencoder parameterized by a novel graph neural network architecture, which we coin DAG-GNN. In addition to the richer capacity, an advantage of the proposed model is that it naturally handles discrete variables as well as vector-valued ones. We demonstrate that on synthetic data sets, the proposed method learns more accurate graphs for nonlinearly generated samples; and on benchmark data sets with discrete variables, the learned graphs are reasonably close to the global optima. The code is available at \url{this https URL}. <<<

Though sertraline is commonly prescribed in patients with major depressive disorder (MDD), its superiority over placebo is only marginal. This is in part due to the neurobiological heterogeneity of the individuals. Characterizing individual-unique functional architecture of the brain may help better dissect the heterogeneity, thereby defining treatment-predictive signatures to guide personalized medication. In this study, we investigate whether individualized brain functional connectivity (FC) can define more predictable signatures of antidepressant and placebo treatment in MDD. The data used in the present work were collected by the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study. Patients (N = 296) were randomly assigned to antidepressant sertraline or placebo double-blind treatment for 8 weeks. The whole-brain FC networks were constructed from pre-treatment resting-state functional magnetic resonance imaging (rs-fMRI). Then, FC was individualized by removing the common components extracted from the raw baseline FC to train regression-based connectivity predictive models. With individualized FC features, the established prediction models successfully identified signatures that explained 22% variance for the sertraline group and 31% variance for the placebo group in predicting HAMD change. Compared with the raw FC-based models, the individualized FC-defined signatures significantly improved the prediction performance, as confirmed by cross-validation. For sertraline treatment, predictive FC metrics were predominantly located in the left middle temporal cortex and right insula. For placebo, predictive FC metrics were primarily located in the bilateral cingulate cortex and left superior temporal cortex. Our findings demonstrated that through the removal of common FC components, individualization of FC metrics enhanced the prediction performance compared to raw FC. Associated with previous MDD clinical studies, our identified predictive biomarkers provided new insights into the neuropathology of antidepressant and placebo treatment. <<<

Xiao Guo, Yuemeng Zhu, Lu Guo, Yiwen Qi, Xiaocheng Liu, Jinhui Wang, Jiangtao Zhang, Linlin Cui, Yueyang Shi, Qichu Wang, Cenxi Liu, Guangxing Lu, Yilian Liu, Tao Li, Shangyu Hong, Yingying Qin, Xuelian Xiong, Hao Wu, Lin Huang, He Huang, Chao Gu, Bin Li, Jin Li <<<

Premature ovarian insufficiency (POI) is a disease featured by early menopause before 40 years of age, accompanied by an elevation of follicle-stimulating hormone. Though POI affects many aspects of women's health, its major causes remain unknown. Many clinical studies have shown that POI patients are generally underweight, indicating a potential correlation between POI and metabolic disorders. To understand the pathogenesis of POI, we performed metabolomics analysis on serum and identified branch-chain amino acid (BCAA) insufficiency-related metabolic disorders in two independent cohorts from two clinics. A low BCAA diet phenotypically reproduced the metabolic, endocrine, ovarian, and reproductive changes of POI in young C57BL/6J mice. A mechanism study revealed that the BCAA insufficiency-induced POI is associated with abnormal activation of the ceramide-reactive oxygen species (ROS) axis and consequent impairment of ovarian granulosa cell function. Significantly, the dietary supplement of BCAA prevented the development of ROS-induced POI in female mice. The results of this pathogenic study will lead to the development of specific therapies for POI. <<<

Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cellular membrane. Recently, eCISs have been found to target mouse cells, raising the possibility that these systems could be harnessed for therapeutic protein delivery. However, whether eCISs can function in human cells remains unknown, and the mechanism by which these systems recognize target cells is poorly understood. Here we show that target selection by the Photorhabdus virulence cassette (PVC)-an eCIS from the entomopathogenic bacterium Photorhabdus asymbiotica-is mediated by specific recognition of a target receptor by a distal binding element of the PVC tail fibre. Furthermore, using in silico structure-guided engineering of the tail fibre, we show that PVCs can be reprogrammed to target organisms not natively targeted by these systems-including human cells and mice-with efficiencies approaching 100%. Finally, we show that PVCs can load diverse protein payloads, including Cas9, base editors and toxins, and can functionally deliver them into human cells. Our results demonstrate that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy and biocontrol. <<<

Bob Chen, Cherie' R Scurrah, Eliot T McKinley, Alan J Simmons, Marisol A Ramirez-Solano, Xiangzhu Zhu, Nicholas O Markham, Cody N Heiser, Paige N Vega, Andrea Rolong, Hyeyon Kim, Quanhu Sheng, Julia L Drewes, Yuan Zhou, Austin N Southard-Smith, Yanwen Xu, James Ro, Angela L Jones, Frank Revetta, Lynne D Berry, Hiroaki Niitsu, Mirazul Islam, Karin Pelka, Matan Hofree, Jonathan H Chen, Siranush Sarkizova, Kimmie Ng, Marios Giannakis, Genevieve M Boland, Andrew J Aguirre, Ana C Anderson, Orit Rozenblatt-Rosen, Aviv Regev, Nir Hacohen, Kenta Kawasaki, Toshiro Sato, Jeremy A Goettel, William M Grady, Wei Zheng, M Kay Washington, Qiuyin Cai, Cynthia L Sears, James R Goldenring, Jeffrey L Franklin, Timothy Su, Won Jae Huh, Simon Vandekar, Joseph T Roland, Qi Liu, Robert J Coffey, Martha J Shrubsole, Ken S Lau <<<

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC. <<<

Differentiating neutrophils undergo large-scale changes in nuclear morphology. How such alterations in structure are established and modulated upon exposure to microbial agents is largely unknown. Here, we found that prior to encounter with bacteria, an armamentarium of inflammatory genes was positioned in a transcriptionally passive environment suppressing premature transcriptional activation. Upon microbial exposure, however, human neutrophils rapidly (<3 h) repositioned the ensemble of proinflammatory genes toward the transcriptionally permissive compartment. We show that the repositioning of genes was closely associated with the swift recruitment of cohesin across the inflammatory enhancer landscape, permitting an immediate transcriptional response upon bacterial exposure. We found that activated enhancers, marked by increased deposition of H3K27Ac, were highly enriched for cistromic elements associated with PU.1, CEBPB, TFE3, JUN, and FOSL2 occupancy. These data reveal how upon microbial challenge the cohesin machinery is recruited to an activated enhancer repertoire to instruct changes in chromatin folding, nuclear architecture, and to activate an inflammatory gene program. <<<

An ultrasonic imaging technique has been developed to investigate the internal changes of pouch cells nondestructively. The local ultrasonic transmittance of pouch cells has been measured and used for imaging with a new ultrasonic scanning machine designed and built in-house. The wetting process of the cells is clearly observed via such ultrasonic imaging techniques. Furthermore, ultrasonic transmission images of fresh cells and aged cells with different electrolytes and cycling conditions exhibit very different ultrasonic transmittance, which can be caused by electrolyte dry-out or “unwetting” due to cell swelling. The ultrasonic imaging technique is a very sensitive method to probe failure mechanisms in Li-ion pouch cells. <<<

Rongjie Cheng, Fanying Li, Maolei Zhang, Xin Xia, Jianzhuang Wu, Xinya Gao, Huangkai Zhou, Zhi Zhang, Nunu Huang, Xuesong Yang, Yaliang Zhang, Shunli Shen, Tiebang Kang, Zexian Liu, Feizhe Xiao, Hongwei Yao, Jianbo Xu, Chao Yan, Nu Zhang <<<

Mutations of the RAS oncogene are found in around 30% of all human cancers yet direct targeting of RAS is still considered clinically impractical except for the KRAS mutant. Here we report that RAS-ON (RASON), a novel protein encoded by the long intergenic non-protein coding RNA 00673 (LINC00673), is a positive regulator of oncogenic RAS signaling. RASON is aberrantly overexpressed in pancreatic ductal adenocarcinoma (PDAC) patients, and it promotes proliferation of human PDAC cell lines in vitro and tumor growth in vivo. CRISPR/Cas9-mediated knockout of Rason in mouse embryonic fibroblasts inhibits KRAS-mediated tumor transformation. Genetic deletion of Rason abolishes oncogenic KRAS-driven pancreatic and lung cancer tumorigenesis in LSL-Kras; Trp53 mice. Mechanistically, RASON directly binds to KRAS and inhibits both intrinsic and GTPase activating protein (GAP)-mediated GTP hydrolysis, thus sustaining KRAS in the GTP-bound hyperactive state. Therapeutically, deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells and patient-derived organoids to EGFR inhibitors. Our findings identify RASON as a critical regulator of oncogenic KRAS signaling and a promising therapeutic target for KRAS mutant cancers. <<<