Biology subjects

Wu, J. Q.

Publications and source records attributed to Wu, J. Q..

5 recordsLinked to original sources

bioRxiv2025

KRAS withdrawal in Cholangiocarcinoma leads to immune infiltration and tumor regression

Background and AimsCholangiocarcinoma (CCA) is a liver cancer with poor survival rates. Current treatments, including targeted therapies for specific mutations, are limited and benefit only a small subset of patients. KRAS mutations are found in 15-40% of CCA, representing a new potential treatment target. Whether KRAS inhibition leads to CCA tumor regression is unknown partly due to the lack of conditional animal models. Approach and ResultsWe engineered a conditional KrasG12D-driven CCA mouse model by co-delivering plasmids encoding the Sleeping Beauty transposase with a luciferase reporter, a transposon-borne inducible KrasG12D transgene and Cas9 and Trp53 guide RNA into mouse liver by hydrodynamic tail-vein injection. In vivo bioluminescent imaging showed that KrasG12D withdrawal resulted in 99% tumor regression by day 7. KrasG12D withdrawal resulted in infiltration of activated CD8+ T cells by IHC and IF staining. Single cell RNA-Seq result also validated the enrichment of activated CD8+ T cells subpopulation in KrasG12D-withdrawn tumor. RNA-Seq suggested that KrasG12D withdrawal stimulated transforming growth factor beta pathway and induced senescence. We used cytokine array to characterize the secretion of pro-inflammatory factors, including IL-15 and Ccl17, upon KrasG12D withdrawal. Lentiviral overexpression of murine CCL17 delayed CCA tumor progression in a xenograft model, and overexpression of murine IL-15 resulted in tumor regression in a transplant model. Flow cytometry analysis revealed that IL-15 and CCL17 recruited and activated CD8+ T cells in CCA tumor. Expression of IL-15 resulted in blockade of tumor progression in our TKP CCA model. ConclusionsKrasG12D withdrawal results in rapid tumor regression, highlighting the importance of oncogenic Kras in CCA tumor maintenance. KrasG12D withdrawal induces p53-independent senescence, secretion of pro-inflammatory factors, and immune surveillance by activated CD8+ T cells. We identified two secreted factors IL-15 and CCL17 that could recruit and activate T cells and control CCA tumor progression. This study underscores KRAS inhibition as a potential therapeutic approach for CCA.

cancer biology↗

bioRxiv2024

PRMT5 orchestrates EGFR and AKT networks to activate NFκB and promote EMT

Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities in children. Despite advancements in combinatorial and targeted treatments improving survival rates, nearly 50% of patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation of the epithelial-mesenchymal transition (EMT) is a key mechanism of tumor cell dissemination, resulting in metastasis and poor outcomes in many cancers. Our prior work identified PRMT5 as a key regulator of EMT via methylation of AKT at arginine 15, enhancing the expression of EMT-driving transcription factors and facilitating metastasis. Here, we identify that PRMT5 directly regulates the transcription of the epidermal growth factor receptor (EGFR). PRMT5, through independent modulation of the EGFR and AKT pathways, orchestrates the activation of NF{kappa}B, resulting in the upregulation of the pro-EMT transcription factors ZEB1, SNAIL, and TWIST1. Notably, EGFR and AKT form a compensatory feedback loop, reinforcing the expression of these EMT transcription factors. Small molecule inhibition of PRMT5 methyltransferase activity disrupts EGFR/AKT signaling, suppresses EMT transcription factor expression and ablates tumor growth in vivo. Our findings underscore the pivotal role of PRMT5 in the control of the EMT program in high-risk neuroblastoma.

cancer biology↗

bioRxiv2020

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

BACKGROUNDSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODSWe conducted the largest to date genome-wide genotype-by-sex (GxS) interaction of risk for these disorders, using 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTSAcross disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes implicating neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) implicating various functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONSIn the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

genetics↗

bioRxiv2020

Protein arginine methyltransferase 5 promotes metastasis via enhancing EGFR transcription and modulating AKT1 activation by methylation

Protein arginine methyltransferase 5 (PRMT5) regulates a wide range of physiological processes, including cancer cell proliferation and metastasis, by generating symmetric di-methyl-arginine marks on histones and non-histone proteins. Here, we report that PRMT5 directly regulates epidermal growth factor receptor (EGFR) transcription to control EGF stimulated EGFR signaling. Furthermore, PRMT5 modulates protein kinase B (AKT) activation by methylation of AKT1 Arg 15, which is required for its subsequent phosphorylation at AKT1 Thr 308 and Ser 473. The PRMT5/EGFR/AKT axis converges to regulate transcription factors ZEB1, SNAIL, and TWIST1 to promote the epithelial-mesenchymal transition (EMT), in the manner that EGFR and AKT1 compensate each other to support tumor cell invasion and metastasis. Inhibiting PRMT5 methyltransferase activity with a small molecule inhibitor attenuated primary tumor growth and prevented hepatic metastasis in aggressive in vivo tumor models. Collectively, our results support the use of PRMT5 based therapies for metastatic cancer.

cancer biology↗

bioRxiv2019

Dissecting the first phased dikaryotic genomes of the wheat rust pathogen Puccinia triticina reveals the mechanisms of somatic exchange in nature

Although somatic hybridization (SH) has been proposed as a means of accelerating rust pathogen virulence evolution in the absence of sexual recombination, previous studies are limited to the laboratory and none have revealed how this process happens. Using long-read sequencing, we generated dikaryotic phased genomes and annotations for three Australian field-collected isolates of the wheat leaf rust pathogen (Puccinia triticina; Pt), including a putative asexual hybrid (Pt64) and two putative parental isolates (Pt104 and Pt53; 132-141 Mb,155-176 contigs, N50 of 1.9-2.1 Mb). The genetic dissection based on the high-quality phased genomes including whole-genome alignments, phylogenetic and syntenic analyses along with short-read sequencing of 27 additional Pt isolates convergently demonstrated that Pt64, which rendered several commercial hybrid wheat cultivars susceptible to leaf rust, arose from SH between isolates within the Pt53 and Pt104 lineages. Parentage analysis demonstrated the role of mitotic crossover in the derivation of both nuclei of Pt64. Within HD mating type genes, the distinct specificity regions in Pt64 and the distinct phylogenetic pattern of the remaining admixed isolates suggested high genetic variation in specificity-related regions on the b locus intrinsically associated with the SH. This study not only provided a fundamental platform for investigating genomic variation underlying virulence evolution in one of the most devastating wheat pathogens, but also offered an in-depth understanding of the mechanisms of naturally occurring SH. This asexual mechanism can be broadly exploited by any dikaryotic pathogen to accelerate virulence evolution, and understanding this process is both urgent and crucial for sustainable pathogen control.\n\nImportanceStrategies to manage plant rust pathogens are challenged by the constant emergence of new virulence. Although somatic hybridization has been proposed as a means by which rusts could overcome host resistance rapidly and cause crop loss, there is very little evidence of this process in nature and the mechanisms underlying it are not known. This study generated and analysed the first dikaryotic phased genomes of the wheat leaf rust pathogen, identifying an isolate as a hybrid and for the first time unveiling parasexuality via mitotic crossover in a rust pathogen. The erosion of the resistance of several hybrid wheat cultivars in agriculture by the hybrid rust has important implications for breeding efforts targeting durable resistance and sustained rust control.

microbiology↗