Biology subjects

Lin, S.-Y.

Publications and source records attributed to Lin, S.-Y..

23 records · Page 2Linked to original sources

bioRxiv2021

Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencing

Esophageal carcinoma is a common and aggressive malignancy, and its patients have dismal clinical outcomes. The epigenetic dysregulation in both major subtypes, esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), awaits further characterization. Here, we perform whole-genome bisulfite sequencing (WGBS) on a total of 43 esophageal cancer and normal samples, generating one of the largest WGBS datasets in this cancer to date. Focusing on hypomethylated regions in cancer, we show that they are associated with increased chromatin activity and enhancer RNA expression. Using this large collection of WGBS dataset, we reveal and validate novel clusters in both ESCC and EAC. We further identify specific molecular features in each cluster, with potential clinical implications. These data together advance our understanding of the epigenetic alterations in esophageal cancer and provide a rich resource for the research community of this disease.

cancer biology↗

bioRxiv2021

Pancreatic Brsk2 amplifies parasympathetic signals to promote type 2 diabetes

The parasympathetic nervous system (PNS) modulates postprandial glucose metabolism via innervating pancreas; however, its significance in the pathogenesis of type 2 diabetes (T2DM) remains unclear. Here we show that brain-specific serine/threonine-protein kinase 2 (Brsk2), accumulated in obese mouse islets, responds to PNS activation and initiates pre-absorptive insulin release. In inducible mouse models, excessive Brsk2 amplifies parasympathetic signaling to {beta} cells and increases their secretion, ensuing insulin resistance and T2DM. Conversely, Brsk2 inhibition prevents and treats HFD-induced metabolic abnormities via avoiding {beta}-cell oversecretion. Mechanistically, parasympathetic acetylcholine activates cholinergic receptor M3 (Chrm3), then Chrm3 recruits and stabilizes Brsk2, which in turn phosphorylates phospholipase A2 activating protein (Plaa). A Chrm3-Brsk2-Plaa axis stimulates {beta}-cell hypersecretion during both pre-absorptive and absorptive stages in HFD-feeding mice, thus imposing insulin resistance and {beta}-cell dysfunction. Blocking parasympathetic signaling to {beta} cells by Brsk2 protein restoration, autonomic mediation drugs, or vagotomy restricted diabetes development. Moreover, three human BRSK2 variants are associated with hyperinsulinemia, insulin resistance, and T2DM in the Chinese population. These findings reveal that Brsk2 links parasympathetic nervous system to nutrition-overload induced T2DM.

pathology↗

bioRxiv2020

Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

{gamma}{delta} T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune systems and can attack cancer or virus-infected cells in an MHC-unrestricted manner. Despite its antitumor ability in both autologous and allogeneic settings, earlier trials of adoptive {gamma}{delta} T cell transfer in solid tumors had limited success due to limitations in cell expansion and the lack of a strategy to modulate tumor lytic interactions between {gamma}{delta} T and cancer cells. Here, we show through quantitative surface proteomics and gene enrichment analyses that DNA methyltransferase inhibitors (DNMTis) upregulate multiple surface molecules related to {gamma}{delta} T cell activation in cancer cells. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded {gamma}{delta} T cells using a clinical-grade expansion protocol developed by our team to enrich for the V{delta}1 subset while preserving their antitumor effector functions. Mechanistically, DNMTis enhance immune synapse formation and stabilize the synaptic cleft to facilitate {gamma}{delta} T-mediated tumor lysis. Through integrated analysis of RNA-seq, DNA methylation, and ATAC-seq, we demonstrate that depletion of DNMTs induces coordinated pattern alterations of immune synaptic-cytoskeletal networks at the cancer side of the immune synapse. In addition, single-cell mass cytometry reveals enrichment of polyfunctional {gamma}{delta} T subsets by DNMTis. Combined DNMTi and adoptive {gamma}{delta} T transfer in a mouse lung cancer model offers a significant survival benefit. Consistently, the DNMTi-associated cytoskeleton signature identifies a subset of lung cancer patients with improved survival. Our results demonstrate that epigenetic mechanisms are crucial for cytoskeletal remodeling in cancer to potentiate immune attack and support a combinatorial strategy of DNMTis and {gamma}{delta} T cell-based immunotherapy in lung cancer management. One Sentence SummaryDNA methyltransferase inhibitors potentiate the killing of lung cancer by {gamma}{delta} T cells through remodeling cytoskeletal-immune synaptic networks.

cancer biology↗

bioRxiv2019

Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma

Aberrant fucosylation plays a critical role in lung cancer progression. Identification of the key fucosyltransferase as a therapeutic target may refine lung cancer management. Here, we identified a terminal 1,3-fucosyltransferase, FUT4, as the key prognostic predictor for lung adenocarcinoma through transcriptomic screens in lung cancer cohorts. Overexpression of FUT4 promotes lung cancer invasion, migration and cell adhesion in vitro and provokes distant metastases in mouse xenograft models. RNA-seq and glycoproteomics analyses revealed that FUT4 mediates aberrant fucosylation of intracellular transport and signal transduction proteins, which facilitates concurrent transcriptional activation of multiple cellular processes, including membrane trafficking, cell cycle, and major oncogenic signaling pathways. Notably, knockdown of FUT4 markedly curtailed lung colonization and distant metastases of lung cancer cells in mouse xenograft models. In addition, the metastatic phenotype provoked by FUT4-mediated fucosylproteomic networks can be diminished by targeted pathway inhibitors. Collectively, FUT4 represents a promising therapeutic target in lung cancer metastasis. Our data highlight the potentials for integration of glycomics into precision medicine-based therapeutics.

cancer biology↗

bioRxiv2019

Comparison of Escherichia coli surface attachment methods for single-cell, in vivo microscopy

For in vivo, single-cell imaging bacterial cells are commonly immobilised via physical confinement or surface attachment. Different surface attachment methods have been used both for atomic force and optical microscopy (including super resolution), and some have been reported to affect bacterial physiology. However, a systematic comparison of the effects these attachment methods have on the bacterial physiology is lacking. Here we present such a comparison for bacterium Escherichia coli, and assess the growth rate, size and intracellular pH of cells growing attached to different, commonly used, surfaces. We demonstrate that E. coli grow at the same rate, length and internal pH on all the tested surfaces when in the same growth medium. The result suggests that tested attachment methods can be used interchangeably when studying E. coli physiology.

systems biology↗