Biology subjects

Tu, M.

Publications and source records attributed to Tu, M..

7 recordsLinked to original sources

bioRxiv2026

Co-evolution of Oncogenic KRAS Signaling and LILRBhigh Macrophages Drives Pancreatic Cancer Recurrence

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after surgical resection, indicating that residual disease is sustained by coordinated tumor-microenvironment interactions. To define the biological basis of recurrence, we leverage large-scale clinical data from 2,710 patients, deeply characterized multi-omics profiling (whole-exome, bulk RNA, and single-nucleus sequencing) of 36 matched primary and locally recurrent PDACs, an in-house multiplex spatial imaging cohort of 190 patients, and extensive public datasets. Recurrent tumors were characterized by increased KRAS mutant allele dosage and reinforced KRAS signaling, accompanied by expansion of basal-like malignant cell states. In parallel, we identified an immunosuppressive macrophage population marked by high LILRB expression that spatially co-localized with KRAS-activated tumor cells. Functional studies showed that LILRB4+ macrophages enhanced tumor cell plasticity and progression, whereas inhibition of macrophage LILRB4 suppressed these phenotypes. Notably, a first-in-class human anti-LILRB4 antibody reduced macrophage-driven tumor traits, and dual targeting of KRAS signaling and LILRB4 achieved superior tumor control in macrophage-containing mouse models. These findings reveal a co-evolved tumor-immune niche underlying PDAC recurrence and nominate the KRAS-LILRB4 axis as a therapeutic vulnerability.

cancer biology↗

bioRxiv2024

Nutrient competition predicts gut microbiome restructuring under drug perturbations

Human gut commensal bacteria are routinely exposed to various stresses, including therapeutic drugs, and collateral effects are difficult to predict. To systematically interrogate community-level effects of drug perturbations, we screened stool-derived in vitro communities with 707 clinically relevant small molecules. Across [~]5,000 community-drug interaction conditions, compositional and metabolomic responses were predictably impacted by nutrient competition, with certain species exhibiting improved growth due to adverse impacts on competitors. Changes to community composition were generally reversed by reseeding with the original community, although occasionally species promotion was long-lasting, due to higher-order interactions, even when the competitor was reseeded. Despite strong selection pressures, emergence of resistance within communities was infrequent. Finally, while qualitative species responses to drug perturbations were conserved across community contexts, nutrient competition quantitatively affected their abundances, consistent with predictions of consumer-resource models. Our study reveals that quantitative understanding of the interaction landscape, particularly nutrient competition, can be used to anticipate and potentially mitigate side effects of drug treatment on the gut microbiota.

microbiology↗

bioRxiv2023

Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response via AP1 dichotomy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity. This intratumoral co-existence of classical and basal-like programs is evident in multi-scale transcriptomic and spatial analyses of resected, advanced-stage and chemotherapy-treated specimens and reciprocally linked to a diverse stromal immune microenvironment as well as worse clinical outcome. However, the underlying mechanisms of intratumoral subtype heterogeneity remain largely unclear. Here, by combining preclinical models, multi-center clinical, bulk and compartment-specific transcriptomic, proteomic, and bioimaging data from human specimens, we identified an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic CD68+ macrophages as a driver of intratumoral subtype co-existence along with an immunosuppressive tumor microenvironment with T cell exclusion. Our ATAC-, ChIP-, and RNA-seq analyses revealed that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory immune signatures in tumor cells, antagonizing cJUN/AP1 signaling to favor a therapy-responsive classical neoplastic identity. Through the tumor microenvironment, this dichotomous regulation was further amplified via regional macrophage populations. Moreover, CD68+/TNF-+ cells associated with a reactive phenotype and reduced CD8+ T cell infiltration in human PDAC tumors. Consequently, combined anti-TNF- immunotherapy and chemotherapy resulted in reduced macrophage counts and promoted CD3+/CD8+ T cell infiltration in basal-like PDAC, leading to improved survival in preclinical murine models. We conclude that tumor cell intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.

cancer biology↗

bioRxiv2023

Neutrophil-derived complement factor P induces cytotoxicity in basal-like cells via caspase 3/7 activation in pancreatic cancer

Due to profound heterogeneity within stromal immune tumor microenvironment (TME), pancreatic ductal adenocarcinoma (PDAC) remains a hard to treat disease, with the lowest 5-year survival below 10%. Large-scale transcriptomic analysis has revealed two main, clinically relevant PDAC signatures: therapy responsive Classical subtype with better prognosis, and poorly-differentiated Basal-like with poor prognosis. It has also become evident that the cellular and humoral components in the immune TME considerably influence the outcome of tumorigenesis. Complement system, a potent humoral innate immune mechanism, also forms a part of this immune TME. In addition to the regular production of various complement components in the liver, certain infiltrating immune cells such as macrophages, dendritic cells and neutrophils, can produce a few complement components locally at the site of infection and inflammation including TME, and modulate tumorigenic outcomes. Neutrophils are the most prevalent innate immune cells in the PDAC TME; however, its role has been attributed as either pro-tumorigenic or anti-tumorigenic. Neutrophils, when stimulated or under stress, are capable of releasing their secretory granules that also contain the only known up-regulator of the complement alternative pathway, Complement Factor P (CFP) or properdin. Properdin can not only facilitate alternative pathway activation by stabilising the C3 convertase, but also act as a pattern recognition receptor on its own and modify inflammatory response. Here, by combining multicenter transcriptome analysis of PDAC patient tumors, single-cell-RNA-seq analysis, preclinical mouse models and human PDAC specimens, we show that properdin expression and neutrophil surveillance are linked to better prognosis in PDAC patients. Furthermore, properdin expression is substantially higher in well-to-moderately differentiated Classical subtype compared to the highly aggressive basal-like PDAC tumours. Mechanistically, exogenous properdin binds to the cell membrane and activates caspase 3/7 to induce apoptosis in basal-like PDAC cells. Together, these findings suggest that the complement protein, properdin, could be a favorable prognostic factor and exhibit anti-tumorigenic functions in PDAC.

immunology↗

bioRxiv2023

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates the axon guidance genes robo2 and slit in Drosophila

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.

neuroscience↗

bioRxiv2021

Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate

Glycogen synthase (GYS1), in complex with glycogenin (GYG1), is the central enzyme of muscle glycogen biosynthesis, and its inhibition has been proposed as a therapeutic avenue for various glycogen storage diseases (GSDs). GYS1 activity is inhibited by phosphorylation of its N- and C-termini, which can be relieved by allosteric activation of glucose-6-phosphate. However, the structural basis of GYS1 regulation is unclear. Here, we present the first cryo-EM structures of phosphorylated human GYS1 complexed with a minimal interacting region of GYG1 in the inhibited, activated, and catalytically competent states at resolutions of 3.0-4.0 [A]. These structures reveal how phosphorylations of specific N- and C- terminal residues are sensed by different arginine clusters that lock the GYS1 tetramer complex in an inhibited state via inter-subunit interactions. The allosteric activator, glucose-6-phopshate, promotes a conformational change by disrupting these interactions and increases flexibility of GYS1 allowing for a catalytically competent state to occur when bound to the sugar donor UDP-glucose. We also identify an inhibited-like conformation that has not transitioned into the activated state, whereby the locking interaction of phosphorylation with the arginine cluster impedes the subsequent conformational changes due to glucose-6-phosphate binding. Finally, we show that the PP1 phosphatase regulatory subunit PPP1R3C (PTG) is recruited to the GYS1:GYG1 complex through direct interaction with glycogen. Our results address long-standing questions into the mechanism of human glycogen synthase regulation.

biochemistry↗

bioRxiv2017

VlbZIP30 of grapevine functions in drought tolerance via the abscisic acid core signaling pathway

Drought stress limits the growth and development of grapevines, thereby reducing productivity, but the mechanisms by which grapevines respond to drought stress remain largely uncharacterized. Here, we characterized a group A bZIP gene from Kyoho grapevine, VlbZIP30, which was shown to be induced by abscisic acid (ABA) and dehydration stress. Overexpression of VlbZIP30 in transgenic Arabidopsis enhanced dehydration tolerance during seed germination, and in the seedling and adult stages. Transcriptome analysis revealed that a major proportion of ABA- and/or drought-responsive genes are transcriptionally regulated by VlbZIP30 during ABA or mannitol treatment at the cotyledon greening stage. We identified an A. thaliana G-box motif (CACGTG) and a potential grapevine G-box motif (MCACGTGK) in the promoters of the 39 selected A. thaliana genes up-regulated in the transgenic plants and in the 35 grapevine homologs, respectively. Subsequently, using two grapevine-related databases, we found that 74% and 84% (a total of 27 genes) of the detected grapevine genes were significantly up-regulated by ABA and drought stress, respectively, suggesting that these 27 genes involve in ABA or dehydration stress and may be regulated by VlbZIP30 in grapevine. We propose that VlbZIP30 functions as a positive regulator of drought-responsive signaling in the ABA core signaling pathway.\n\nHighlightVlbZIP30 positively regulate plant drought tolerance through regulated the expression of 27 grapevine candidate genes via G-box cis-element (MCACGTGK) in ABA signaling pathway.

plant biology↗