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Updated: Aug 28, 2025
Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts
Published on: April 29, 2014
Single-cell profiling reveals molecular basis of malignant phenotypes and tumor microenvironments in small bowel
Jingwei Yang1,2, Xin Zhou1,3, Ji Dong4
1School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing, China.
Abstract:
Small bowel adenocarcinomas (SBAs) are rare malignant tumors with a high mortality rate, and their molecular characteristics are still largely unexplored. Here we performed single-cell RNA sequencing for tumor samples from 12 SBA patients and predicted drug candidates for SBA. We identified four prevalent subtypes of malignant cells with distinct signatures including cell cycle program, mitochondria program, metabolism program and epithelial-mesenchymal transition (EMT) program. The progression relationships of these four subtypes of malignant cells were also revealed, which started from the cell cycle program, through the mitochondria program and then progressing into either the metabolism program or the EMT program. Importantly, ligand-receptor interaction pairs were found to be specifically enriched in pairs of EMT-program malignant cells and highly exhausted CD8+ T cells, suggesting that cancer cell subpopulations with EMT features may contribute most to the exhaustion of T cells. We also showed that the duodenal subtype of SBA exhibited molecular features more similar to gastric cancer whereas jejunal subtype of SBA more similar to colorectal cancer. Especially, we predicted specific drugs for SBA based on differential gene expression signatures between malignant cells and normal epithelial cells of SBA, and verified more potent inhibitory effects of volasertib and tozasertib for SBA cancer cells than conventional drugs of SBA at the same concentration, which provides new clues for treatments of SBA. In summary, our study provides a blueprint of the molecular signatures of both tumor cells and tumor microenvironment cells in SBA and reveals potential targets and drug candidates for its clinical treatments.
Insights
This study reveals four malignant cell subtypes in small bowel adenocarcinomas (SBAs) and their progression. Researchers identified potential drug candidates, volasertib and tozasertib, offering new treatment avenues for this rare cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Small bowel adenocarcinomas (SBAs) are rare and aggressive gastrointestinal cancers with poorly understood molecular features and high mortality.
- Existing research on SBA molecular characteristics and therapeutic targets remains limited, hindering effective treatment strategies.
Purpose of the Study:
- To elucidate the molecular subtypes and cellular dynamics within SBAs using single-cell RNA sequencing.
- To identify potential therapeutic targets and novel drug candidates for SBA treatment.
- To investigate the interactions between tumor cells and the tumor microenvironment, specifically T-cell exhaustion.
Main Methods:
- Single-cell RNA sequencing was performed on tumor samples from 12 SBA patients.
- Computational analysis was used to identify distinct malignant cell subtypes and their progression pathways.
- Ligand-receptor interactions were analyzed to understand cell-cell communication within the tumor microenvironment.
- Differential gene expression analysis was employed to predict and validate potential drug candidates.
Main Results:
- Four prevalent malignant cell subtypes were identified, characterized by distinct molecular programs (cell cycle, mitochondria, metabolism, EMT).
- A progression model was established, showing a pathway from cell cycle to metabolism or EMT programs.
- Specific ligand-receptor interactions were enriched between EMT-program cells and exhausted CD8+ T cells, suggesting a role in T-cell exhaustion.
- Duodenal SBAs showed molecular similarities to gastric cancer, while jejunal SBAs resembled colorectal cancer.
- Volasertib and tozasertib demonstrated potent inhibitory effects on SBA cancer cells, outperforming conventional drugs.
Conclusions:
- This study provides a comprehensive molecular blueprint of SBA, including tumor cells and the tumor microenvironment.
- The identified malignant cell subtypes and progression pathways offer insights into SBA pathogenesis.
- The findings highlight potential therapeutic targets and specific drug candidates, such as volasertib and tozasertib, for SBA treatment.
- Understanding subtype-specific molecular features may guide personalized treatment approaches for duodenal versus jejunal SBAs.
