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Updated: Jul 13, 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
Cancer-associated fibroblasts undergoing neoadjuvant chemotherapy suppress rectal cancer revealed by single-cell and
Pengfei Qin1, Huaxian Chen2, Yuhang Wang3
1BGI Research, Shenzhen 518083, China; BGI Research, Chongqing 401329, China.
Abstract:
Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF_FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs.
Insights
Neoadjuvant chemotherapy remodels the rectal cancer tumor microenvironment by reshaping cancer-associated fibroblasts (CAFs). These changes activate anti-tumor immunity and suppress tumor growth, improving therapeutic response.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Neoadjuvant chemotherapy (NAC) shows promise for rectal cancer (RC).
- The impact of NAC on the tumor microenvironment (TME) and its link to treatment outcomes are not fully understood.
Purpose of the Study:
- To investigate the cellular dynamics and TME alterations induced by NAC in RC patients.
- To identify the association between TME modulation and therapeutic response to NAC.
Main Methods:
- Single-cell RNA sequencing and spatial transcriptome sequencing were employed.
- Paired tumor samples from 29 RC patients before and after NAC were analyzed.
Main Results:
- NAC significantly reshaped cancer-associated fibroblast (CAF) populations, correlating strongly with therapeutic response.
- Remodeled CAFs activated anti-tumor immunity via cytokines (e.g., CXCL12, SLIT2, DCN).
- CAF-FAP upregulated epithelial-mesenchymal transition in malignant cells via MIR4435-2HG, leading to poorer outcomes.
Conclusions:
- NAC effectively inhibits RC progression by remodeling the TME, particularly CAFs.
- CAF subsets play a critical role in mediating NAC's therapeutic effects and influencing patient outcomes.
