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Updated: Jul 5, 2026
Multiomics Analysis of TMEM200A as a Pan-Cancer Biomarker
Published on: September 15, 2023
Targeting m6A-SCG2-TAMs axis overcomes 5-FU resistance in colorectal cancer via a multi-omics model
Yiming Sun1, Ke Peng1,2, Yuening Li2
1Department of General Surgery, the Second Affiliated Hospital of Army Medical University, Chongqing, China.
Abstract:
Chemoresistance to 5-fluorouracil (5-FU) remains a critical barrier in colorectal cancer (CRC) management. This study integrates multi-omics data from 26,192 human samples to elucidate the RNA methylation-mediated crosstalk between tumor-associated macrophages (TAMs) and tumor cells. Machine learning models were able to effectively stratify patients by risk and identified a core signature of six genes (including SCG2), whose expression patterns were associated with poor prognosis and chemotherapy resistance-related phenotypes. Mechanistically, 5-FU elevates m6A modification in TAMs, polarizing them toward the M2 phenotype. SCG2 mRNA methylation promotes TNF-α ubiquitination, reducing its levels and thereby sustaining NF-κB activation in tumor cells to drive PCD resistance. The core candidate genes (CCGs) model effectively predicts survival outcomes. Targeting SCG2 represents a novel strategy to reverse chemoresistance by disrupting TAMs-tumor crosstalk, offering actionable targets for personalized therapy optimization.
Insights
This study reveals how RNA methylation in tumor-associated macrophages drives 5-fluorouracil chemoresistance in colorectal cancer. Targeting SCG2 may reverse resistance by disrupting this crucial crosstalk.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Chemoresistance to 5-fluorouracil (5-FU) is a major challenge in colorectal cancer (CRC) treatment.
- Tumor-associated macrophages (TAMs) play a significant role in the tumor microenvironment and can influence treatment response.
Purpose of the Study:
- To investigate the role of RNA methylation-mediated crosstalk between TAMs and tumor cells in CRC chemoresistance.
- To identify predictive biomarkers and therapeutic targets for overcoming 5-FU resistance.
Main Methods:
- Integration of multi-omics data from 26,192 human samples.
- Application of machine learning models for patient risk stratification and biomarker identification.
- Mechanistic studies exploring the role of m6A modification and SCG2 in TAM polarization and tumor cell signaling.
Main Results:
- A core signature of six genes, including SCG2, was identified, correlating with poor prognosis and chemoresistance.
- 5-FU treatment increases m6A modification in TAMs, promoting an M2-like phenotype.
- SCG2 mRNA methylation reduces TNF-α levels, enhancing NF-κB activation and promoting paclitaxel-induced cell death (PCD) resistance in tumor cells.
Conclusions:
- SCG2 plays a critical role in mediating TAM-tumor cell crosstalk and driving 5-FU chemoresistance in CRC.
- Targeting SCG2 offers a novel strategy to reverse chemoresistance by disrupting this crosstalk.
- The identified gene signature and SCG2 represent potential targets for personalized CRC therapy.
