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Combined Conditional Knockdown and Adapted Sphere Formation Assay to Study a Stemness-Associated Gene of Patient-derived Gastric Cancer Stem Cells
Published on: May 9, 2020
Transcriptional coexpression network reveals the involvement of varying stem cell features with different
Kalaivani Kalamohan1, Jayaprakash Periasamy1, Divya Bhaskar Rao1
1Cancer Genetics Laboratory, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, India.
Abstract:
Despite the advancements in the cancer therapeutics, gastric cancer ranks as the second most common cancers with high global mortality rate. Integrative functional genomic investigation is a powerful approach to understand the major dysregulations and to identify the potential targets toward the development of targeted therapeutics for various cancers. Intestinal and diffuse type gastric tumors remain the major subtypes and the molecular determinants and drivers of these distinct subtypes remain unidentified. In this investigation, by exploring the network of gene coexpression association in gastric tumors, mRNA expressions of 20,318 genes across 200 gastric tumors were categorized into 21 modules. The genes and the hub genes of the modules show gastric cancer subtype specific expression. The expression patterns of the modules were correlated with intestinal and diffuse subtypes as well as with the differentiation status of gastric tumors. Among these, G1 module has been identified as a major driving force of diffuse type gastric tumors with the features of (i) enriched mesenchymal, mesenchymal stem cell like, and mesenchymal derived multiple lineages, (ii) elevated OCT1 mediated transcription, (iii) involvement of Notch activation, and (iv) reduced polycomb mediated epigenetic repression. G13 module has been identified as key factor in intestinal type gastric tumors and found to have the characteristic features of (i) involvement of embryonic stem cell like properties, (ii) Wnt, MYC and E2F mediated transcription programs, and (iii) involvement of polycomb mediated repression. Thus the differential transcription programs, differential epigenetic regulation and varying stem cell features involved in two major subtypes of gastric cancer were delineated by exploring the gene coexpression network. The identified subtype specific dysregulations could be optimally employed in developing subtype specific therapeutic targeting strategies for gastric cancer.
Insights
This study reveals distinct gene expression patterns in gastric cancer subtypes. Identifying these molecular drivers offers new avenues for developing targeted therapies for diffuse and intestinal gastric tumors.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Gastric cancer remains a leading cause of cancer mortality globally.
- Distinct molecular drivers for intestinal and diffuse gastric tumor subtypes are largely unknown.
- Integrative functional genomics can identify therapeutic targets.
Purpose of the Study:
- To identify subtype-specific molecular determinants in gastric cancer.
- To explore gene coexpression networks for understanding gastric tumor heterogeneity.
- To uncover potential therapeutic targets for distinct gastric cancer subtypes.
Main Methods:
- Analysis of mRNA expression for 20,318 genes across 200 gastric tumors.
- Gene coexpression network construction to identify functional modules.
- Correlation of module expression patterns with gastric cancer subtypes and differentiation status.
Main Results:
- Twenty-one gene coexpression modules were identified, showing subtype-specific expression.
- The G1 module, enriched in mesenchymal features and OCT1/Notch activation, drives diffuse-type gastric tumors.
- The G13 module, associated with stem cell properties and Wnt/MYC/E2F pathways, is key in intestinal-type gastric tumors.
Conclusions:
- Differential transcription programs, epigenetic regulation, and stem cell features characterize gastric cancer subtypes.
- Identified subtype-specific dysregulations provide a basis for targeted therapeutic strategies.
- Understanding molecular heterogeneity is crucial for advancing gastric cancer treatment.
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