Biology subjects

Qiao, K.

Publications and source records attributed to Qiao, K..

6 recordsLinked to original sources

bioRxiv2026

Innate immune sensing via the cGAS-STING pathway restricts extrachromosomal DNA-driven tumorigenesis

Extrachromosomal DNAs (ecDNAs) are circular DNA fragments frequently found in human cancers, where they amplify oncogenes, drive tumor heterogeneity, and promote therapy resistance and poor prognosis. Despite their prevalence, how ecDNAs interact with the immune system remains poorly understood. Here, we show that the cytosolic DNA sensor cGAS detects ecDNA fragments in the cytoplasm and activates the innate immune response. cGAS and STING are frequently silenced in ecDNA+ tumors through promoter hypermethylation. Restoring cGAS or STING in human and murine ecDNA+ cancer cells reactivates innate immune signaling and selectively suppresses ecDNA+ tumor growth in an immunocompetent mouse model. Using two ecDNA biogenesis models, we show that the cGAS-STING pathway restricts de novo ecDNA formation. Together, our findings identify innate immune sensing as a natural barrier to ecDNA-driven oncogenesis and establish cGAS-STING reactivation as a therapeutic strategy for ecDNA+ cancers. HighlightsO_LIThe cGAS-STING pathway is frequently silenced in ecDNA+ tumors C_LIO_LIRestoration of cGAS in ecDNA+ cells activates innate immune responses C_LIO_LIcGAS expression suppresses ecDNA+ tumor growth in vivo C_LIO_LIThe cGAS-STING pathway restricts de novo ecDNA biogenesis C_LI

cancer biology↗

bioRxiv2025

ecDNA-driven oncogene super-expressors shape immunoevasive tumor microenvironment

ecDNA contributes to cancer genetic heterogeneity through random segregation during mitosis. Emerging evidence links ecDNA to immune evasion, but the mechanism remains elusive. Using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC), we show that Kras and Myc oncogenes are amplified either on ecDNAs or as homogeneously staining regions (HSRs) on chromosomes. ecDNA-driven tumors are more aggressive in immunocompetent mice. Single-cell transcriptomic and histological analyses reveal that ecDNA-driven tumors rapidly establish an immunoevasive tumor microenvironment (TME), marked by increased myofibroblastic cancer-associated fibroblasts (myCAFs) and reduced T cell infiltration. Mechanistically, ecDNA heterogeneity generates a subset of cancer cells with extremely high Kras expression, termed super-expressors, which secrete amphiregulin to promote myCAF expansion and suppress T cell infiltration. Clonally organized super-expressors establish an immunoevasive niche in the TME from patients with PDAC. Our findings demonstrate a causal role of ecDNA in TME remodeling, offering insights into cancer heterogeneity and immune evasion.

cancer biology↗

bioRxiv2023

scPharm: identifying pharmacological subpopulations of single cells for precision medicine in cancers

Intratumour heterogeneity is a major challenge that limits the effectiveness of anticancer therapies, thus compromising treatment outcomes. Single-cell RNA sequencing (scRNA-seq) technology offers a means to capture gene expression profiles at a single-cell resolution, while drug perturbation experiments yield valuable pharmacological data at the bulk cell level. Here, we introduce "scPharm", a computational framework to integrate large-scale pharmacogenomics profiles with scRNA-seq data, for identifying pharmacological subpopulations within a tumour and prioritizing tailored drugs. scPharm assesses the distribution of the identity genes of single cell (Cell-ID) within drug response-determined gene list, which is accomplished using the normalized enrichment score (NES) obtained from Gene Set Enrichment Analysis (GSEA) as the statistic. One key strength of scPharm is rooted in the robust positive correlation between NES statistics and drug response values at single-cell resolution. scPharm successfully identifies sensitive subpopulations in ER-positive and HER2-positive human breast cancer tissues, discovers dynamic changes in resistant subpopulation of human PC9 cells treated with Erlotinib, and expands its prediction capabilities to a mouse model. By a thoroughly comparative evaluation with other single-cell prediction tools, scPharm presents the superior predictive performance and computational efficiency. Furthermore, scPharm offers a unique feature by predicting combination strategies, gauging compensation effects or booster effects between two drugs through the Set covering method, as well as evaluating drug toxicity on healthy cells within the tumour microenvironment. Together, scPharm provides a novel approach to uncover therapeutic heterogeneity within tumours at single-cell resolution and facilitates precision medicine in cancers.

bioinformatics↗

bioRxiv2022

Protease inhibitor ASP enhances freezing tolerance by inhibiting protein degradation in Kumquat

Cold acclimation is a complex biological process leading to the development of freezing tolerance in plants. In this study, we demonstrated that cold-induced expression of protease inhibitor FmASP in a citrus relative species kumquat (Fortunella margarita (Lour.) Swingle) contributes to its freezing tolerance by regulating protein degradation. First, we found that only cold-acclimated kumquat plants, although with extensive leaf cellular damage during freezing, are able to resume their normal growth upon stress relief. To dissect the impact of cold acclimation on this extraordinary freezing tolerance, we performed protein abundance assay and quantitative proteomics analysis of kumquat leaves subjected to cold acclimation (4 {degrees}C), freezing treatment (-10 {degrees}C) and post-stress recovery (25 {degrees}C). FmASP and a few non-specific proteases were identified as differentially expressed proteins induced by cold acclimation and associated with stable protein abundance throughout the course of freezing treatment. FmASP was further characterized as a robust inhibitor that inhibits the degradation capacity of multiple proteases. In addition, heterogeneous expression of FmASP in Arabidopsis confirmed its positive function in freezing tolerance. Finally, we proposed a working model of FmASP and illustrated how this extracellular-localized protease inhibitor protects proteins from degradation and consequently maintains essential cellular function for freezing stress recovery. These findings revealed the important role of protease inhibition on freezing response and provide insights on how this role may help develop new strategies to enhance plant freezing tolerance. One-sentence summaryA protease inhibitor of Fortunella margarita enhances protein stability and freezing tolerance by regulating non-specific protease degradation

plant biology↗

bioRxiv2022

PhiPipe: a multi-modal MRI data processing pipeline with test-retest reliability and predicative validity assessments

Magnetic Resonance Imaging (MRI) has been one of the primary instruments to measure the properties of the human brain non-invasively in vivo. MRI data generally needs to go through a series of processing steps (i.e., a pipeline) before statistical analysis. Currently, the processing pipelines for multi-modal MRI data are still rare, in contrast to single-modal pipelines. Furthermore, the reliability and validity of the output of the pipelines are critical for the MRI studies. However, the reliability and validity measures are not available or adequate for almost all pipelines. Here, we present PhiPipe, a multi-modal MRI processing pipeline. PhiPipe could process T1-weighted, resting-state BOLD, and diffusion-weighted MRI data and generate commonly used brain features in neuroimaging. We evaluated the test-retest reliability of PhiPipes brain features by computing intra-class correlations (ICC) in four public datasets with repeated scans. We further evaluated the predictive validity by computing the correlation of brain features with chronological age in three public adult lifespan datasets. The multi-variate reliability and predictive validity of the PhiPipe results were also evaluated. The results of PhiPipe were consistent with previous studies, showing comparable or better reliability and validity when compared with two popular single-modality pipelines, namely DPARSF and PANDA. The publicly available PhiPipe provides a simple-to-use solution to multi-modal MRI data processing. The accompanied reliability and validity assessments could help researchers make informed choices in experimental design and statistical analysis. Furthermore, this study provides a framework for evaluating the reliability and validity of image processing pipelines.

bioinformatics↗

bioRxiv2020

Non-invasive Differentiation of M1 and M2 Activation in Macrophages using Hyperpolarized 13C MRS of Pyruvate and DHA at 1.47 Tesla

Macrophage activation, first generalized to the M1/M2 dichotomy, is a complex and central process of the innate immune response. Simply, M1 describes the classical pro-inflammatory activation, leading to tissue damage, and M2 the alternative activation promoting tissue repair. Given the central role of macrophages in multiple diseases, the ability to non-invasively differentiate between M1 and M2 activation states would be highly valuable for monitoring disease progression and therapeutic responses. Since M1/M2 activation patterns are associated with differential metabolic reprogramming, we hypothesized that hyperpolarized 13C magnetic resonance spectroscopy (HP 13C MRS), an innovative metabolic imaging approach, could distinguish between macrophage activation states noninvasively. The metabolic conversions of HP [1-13C]pyruvate to HP [1-13C]lactate and HP [1-13C]dehydroascorbic acid to HP [1-13C]ascorbic acid were monitored in live M1 and M2 activated J774a.1 macrophages non-invasively by HP 13C MRS on a 1.47 Tesla NMR system. Our results show that both metabolic conversions were significantly increased in M1 macrophages compared to M2 and non-activated cells. Biochemical assays and high resolution 1H MRS were also performed to investigate the underlying changes in enzymatic activities and metabolite levels linked to M1/M2 activation. Altogether, our results demonstrate the potential of HP 13C MRS for monitoring macrophage activation states non-invasively.

biochemistry↗