Prognostic Molecular Pathways in Gastric Cancer

Gastric cancer exhibits marked clinical and molecular heterogeneity, with patient outcomes closely linked to the activation of distinct signalling axes and cellular programmes. Central to prognosis are pathways governing epithelial-to-mesenchymal transition (EMT), immune evasion, DNA repair and growth-factor signalling. Molecular classification schemes have delineated subtypes characterised by differing mutation burdens, microsatellite instability and viral associations, each with unique therapeutic susceptibilities. Key drivers include insulin-like growth factor 1 receptor (IGF1R) and transforming growth factor β (TGF-β) pathways, which promote invasive phenotypes and chemoresistance. Concurrently, receptor tyrosine kinases such as DDR2 underpin peritoneal dissemination, while tumour-associated immune components shape response to immunotherapy. Integrative analyses of genomic, transcriptomic and proteomic datasets are refining prognostic biomarkers and informing personalised treatment. By mapping these prognostic molecular networks, current research aims to stratify patients more precisely, predict therapeutic response and identify novel targets to improve survival in diverse clinical settings.

Research from Nature Portfolio

Recent studies have identified two principal molecular subtypes of gastric adenocarcinoma distinguished by mesenchymal versus epithelial phenotypes. The mesenchymal subtype exhibits low mutation rates, microsatellite stability and pronounced resistance to standard chemotherapy, whereas the epithelial subtype shows higher genomic instability and greater chemosensitivity. Integrative analyses revealed heightened activation of EMT programmes and the IGF1/IGF1R axis in mesenchymal tumours, which demonstrated selective vulnerability to IGF1R inhibition. In a complementary investigation, a peritoneal dissemination-associated gene signature was shown to correlate with extracellular matrix remodelling and focal adhesion processes. Within this signature, upregulation of the receptor tyrosine kinase DDR2—driven by promoter hypomethylation—was found to promote peritoneal metastasis, and pharmacological blockade of DDR2 signalling effectively suppressed dissemination in preclinical models. Together, these foundational findings establish EMT-related growth-factor pathways and DDR2 as promising prognostic indicators and therapeutic targets.

Prognostic Molecular Pathways in Gastric Cancer publication trend

The graph below shows the total number of articles in prognostic molecular pathways in gastric cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Epithelial-to-mesenchymal transition (EMT): A cellular programme by which epithelial cells acquire motile, invasive properties.

Microsatellite instability (MSI): A form of genomic instability characterised by length variations in short tandem DNA repeats.

Tumour microenvironment (TME): The complex milieu of immune cells, stromal elements and signalling molecules surrounding tumour cells.

Consensus genomic subtype (CGS): A classification derived from integrated genomic signatures that captures tumour heterogeneity.

IGF1/IGF1R pathway: A growth-factor signalling axis that regulates proliferation, survival and migration.

Transforming growth factor β (TGF-β) signalling: A pathway that modulates cell differentiation, EMT and immune suppression.

Peritoneal dissemination: Metastatic spread of tumour cells to the peritoneal surfaces lining the abdominal cavity.

Tumour-associated macrophages (TAMs): Macrophages within the TME that can adopt immunosuppressive or pro-tumoural roles.

Ligand–receptor interaction score (LR score): A quantitative measure of potential signalling interactions between cell-surface proteins.

References

1. Clinical and genomic landscape of gastric cancer with a mesenchymal phenotype. Nature Communications (2018).
2. Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination. Scientific Reports (2016).
3. Clinically conserved genomic subtypes of gastric adenocarcinoma. Molecular Cancer (2023).
4. Clinical molecular subtyping reveals intrinsic mesenchymal reprogramming in gastric cancer cells. Experimental & Molecular Medicine (2023).
5. Potential crosstalk between SPP1 + TAMs and CD8 + exhausted T cells promotes an immunosuppressive environment in gastric metastatic cancer. Journal of Translational Medicine (2024).