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Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Machine learning identifies PYGM as a macrophage polarization-linked metabolic biomarker in rectal cancer prognosis
Chengyuan Xu1,2, Siqi Zhang3, Bin Sun2
1Department of General, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China.
Background:
Macrophage polarization plays a pivotal role in shaping the tumor microenvironment and influencing rectal cancer progression. However, the metabolic and prognostic regulators governing this process remain largely undefined.
Methods:
We constructed a macrophage polarization gene signature (MPGS) by integrating weighted gene co-expression network analysis (WGCNA) with multiple machine learning algorithms across two independent cohorts: 363 rectal cancer samples from GSE87211 and 177 samples from The Cancer Genome Atlas (TCGA). The prognostic performance of MPGS was evaluated across rectal and multiple other cancer types. Functional analyses, single-cell RNA sequencing, immunohistochemistry of clinical specimens, and in vitro cellular assays were employed to investigate the role of the MPGS hub gene, PYGM, in tumor biology and immune modulation.
Results:
The MPGS exhibited robust prognostic capability and effectively predicted responses to immunotherapy and various chemotherapeutic agents. Both MPGS and its central metabolic component, PYGM, were closely linked to M2 macrophage infiltration, immunosuppressive tumor microenvironments, and poor clinical outcomes in rectal adenocarcinoma. Single-cell transcriptomic analysis revealed that malignant epithelial cells with elevated PYGM expression are metabolically active and closely interact with M2 macrophages. Clinical tissue analyses and functional assays confirmed that PYGM is upregulated in rectal cancer and promotes tumor cell proliferation, migration, and M2 macrophage polarization.
Conclusions:
This study firstly highlights PYGM as a key metabolic and immunological regulator in rectal cancer, with significant prognostic and therapeutic implications. MPGS and PYGM may serve as novel biomarkers for risk stratification and guide personalized treatment strategies in patients with rectal adenocarcinoma.
Insights
This study identifies PYGM as a key regulator in rectal cancer, linking it to M2 macrophage infiltration and poor outcomes. PYGM and the macrophage polarization gene signature (MPGS) show promise as biomarkers for risk stratification and personalized treatment.
Area of Science:
- Oncology
- Immunology
- Metabolism
Background:
- Macrophage polarization critically influences the rectal cancer tumor microenvironment and progression.
- Metabolic and prognostic regulators of macrophage polarization in rectal cancer are not well understood.
Purpose of the Study:
- To develop a macrophage polarization gene signature (MPGS) for prognostic assessment in rectal cancer.
- To investigate the role of the hub gene PYGM in rectal cancer biology and immune modulation.
Main Methods:
- Constructed MPGS using WGCNA and machine learning on TCGA and GSE87211 rectal cancer cohorts.
- Evaluated MPGS prognostic performance across multiple cancer types.
- Conducted functional analyses, single-cell RNA sequencing, IHC, and in vitro assays to study PYGM.
Main Results:
- MPGS demonstrated strong prognostic capability and predicted immunotherapy/chemotherapy response.
- MPGS and PYGM correlated with M2 macrophage infiltration, immunosuppression, and poor outcomes in rectal adenocarcinoma.
- Elevated PYGM in malignant cells was linked to metabolic activity and M2 macrophage interaction; PYGM promoted proliferation, migration, and M2 polarization.
Conclusions:
- PYGM is identified as a crucial metabolic and immunological regulator in rectal cancer with prognostic and therapeutic significance.
- MPGS and PYGM may serve as novel biomarkers for risk stratification.
- These findings can guide personalized treatment strategies for rectal adenocarcinoma.
