Dataset Information

Immune perturbation network identifies an EMT subtype with chromosomal instability and tumor immune-desert microenvironment.

ABSTRACT: Most gastric cancer (GC) subtypes are identified through transcriptional profiling overlooking dynamic changes and interactions in gene expression. Based on the background network of global immune genes, we constructed sample-specific edge-perturbation matrices and identified four molecular network subtypes of GC (MNG). MNG-1 displayed the best prognosis and vigorous cell cycle activity. MNG-2 was enriched by immune-hot phenotype with the potential for immunotherapy response. MNG-3 and MNG-4 were identified with epithelial-mesenchymal transition (EMT) peculiarity and worse prognosis, termed EMT subtypes. MNG-3 was characterized by low mutational burden and stromal cells and considered a replica of previous subtypes associated with poor prognosis. Notably, MNG-4 was considered a previously undefined subtype with a dismal prognosis, characterized by chromosomal instability and immune-desert microenvironment. This subtype tended to metastasize and was resistant to respond to immunotherapy. Pharmacogenomics analysis showed three therapeutic agents (NVP-BEZ235, LY2606368, and rutin) were potential interventions for MNG-4.

SUBMITTER: Xu H

PROVIDER: S-EPMC10520355 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Immune perturbation network identifies an EMT subtype with chromosomal instability and tumor immune-desert microenvironment.

Xu Hui H Fu Xinyu X Liu Ben B Weng Siyuan S Guo Chunguang C Quan Libo L Liu Long L Wang Libo L Xing Zhe Z Cheng Quan Q Luo Peng P Chen Kexin K Liu Zaoqu Z Han Xinwei X

iScience 20230909 10

Most gastric cancer (GC) subtypes are identified through transcriptional profiling overlooking dynamic changes and interactions in gene expression. Based on the background network of global immune genes, we constructed sample-specific edge-perturbation matrices and identified four molecular network subtypes of GC (MNG). MNG-1 displayed the best prognosis and vigorous cell cycle activity. MNG-2 was enriched by immune-hot phenotype with the potential for immunotherapy response. MNG-3 and MNG-4 wer ...[more]

PMID: 37766999

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Project description:Lysosomes, as primary degradative organelles, are the endpoint of different converging pathways, including macroautophagy. To date, lysosome degradative function has been mainly studied in interphase cells, while their role during mitosis remains controversial. Mitosis dictates the faithful transmission of genetic material among generations, and perturbations of mitotic division lead to chromosomal instability, a hallmark of cancer. Heretofore, correct mitotic progression relies on the orchestrated degradation of mitotic factors, which was mainly attributed to ubiquitin-triggered proteasome-dependent degradation. Here, we show that mitotic transition also relies on lysosome-dependent degradation, as impairment of lysosomes increases mitotic timing and leads to mitotic errors, thus promoting chromosomal instability. Furthermore, we identified several putative lysosomal targets in mitotic cells. Among them, WAPL, a cohesin regulatory protein, emerged as a novel SQSTM1-interacting protein for targeted lysosomal degradation. Finally, we characterized an atypical nuclear phenotype, the toroidal nucleus, as a novel biomarker for genotoxic screenings. Our results establish lysosome-dependent degradation as an essential event to prevent chromosomal instability.Abbreviations: 3D: three-dimensional; APC/C: anaphase-promoting complex; ARL8B: ADP ribosylation factor like GTPase 8B; ATG: autophagy-related; BORC: BLOC-one-related complex; CDK: cyclin-dependent kinase; CENPE: centromere protein E; CIN: chromosomal instability; ConcA: concanamycin A; CQ: chloroquine; DAPI: 4,6-diamidino-2-penylinole; FTI: farnesyltransferase inhibitors; GFP: green fluorescent protein; H2B: histone 2B; KIF: kinesin family member; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTOR: mechanistic target of rapamycin kinase; PDS5B: PDS5 cohesin associated factor B; SAC: spindle assembly checkpoint; PLEKHM2: pleckstrin homology and RUN domain containing M2; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; ULK1: unc-51 like autophagy activating kinase 1; UPS: ubiquitin-proteasome system; v-ATPase: vacuolar-type H+-translocating ATPase; WAPL: WAPL cohesion release factor.

Dataset Information

Immune perturbation network identifies an EMT subtype with chromosomal instability and tumor immune-desert microenvironment.

Publications

Immune perturbation network identifies an EMT subtype with chromosomal instability and tumor immune-desert microenvironment.

Similar Datasets

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