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Updated: Mar 10, 2026
A Three-dimensional Model of Spheroids to Study Colon Cancer Stem Cells
Published on: January 22, 2021
Identification of programmed cell death-related subtypes reveals immune heterogeneity and therapeutic divergence in
Peng Xia1,2, Ying Qu2,3, Quanzhong Liu2,3
1School of Biological Science & Medical Engineering, Southeast University, Nanjing 211189, China.
Rationale:
Therapy resistance remains a critical challenge in colon adenocarcinoma (COAD). The dysregulation of programmed cell death (PCD) pathways significantly influences therapeutic response, but its integrated role in shaping the tumor microenvironment (TME) and driving clinical heterogeneity in COAD is poorly defined.
Methods:
We established a Programmed Cell Death-related Subtype (PCDS) classification by integrating 12 PCD pathways across transcriptomic data from 1,140 COAD patients using non-negative matrix factorization (NMF). The subtypes were validated in independent RNA-sequencing cohorts. We characterized the genomic, TME, and therapeutic features of each PCDS using multi-omics data analysis, and computational drug repositioning. Molecular docking and in silico drug sensitivity analyses were employed to evaluate candidate drugs.
Results:
We identified three robust subtypes, including PCDS1 (immune-activated), PCDS2 (WNT and TP53 signaling activation), and PCDS3 (mesenchymal and T-cell dysfunction/exclusion). PCDS3, enriched with inflammatory cancer-associated fibroblasts (iCAFs), exhibited the poorest prognosis and dual resistance to both chemotherapy and immunotherapy (>80% non-response). Analysis of single-cell and spatial transcriptomics data revealed the activation of MDK-SDC2 ligand-receptor axis between tumor cells and fibroblasts in PCDS3, spatially associated with T-cell dysfunction and exclusion. Computational drug repositioning identified the sunitinib as having selective potency against PCDS3 tumors, showing significantly lower IC50 values and high-affinity binding to SDC2 in molecular docking.
Conclusions:
This study defines a novel molecular subtype for COAD, linking PCD dysregulation to distinct TME remodeling and therapeutic outcomes. Targeting the MDK-SDC2 axis with agents such as sunitinib may offer a promising strategy to overcome stromal-mediated immunotherapy resistance in the most lethal PCDS3 tumors.
Insights
We identified three colon adenocarcinoma subtypes based on programmed cell death (PCD) pathways. One subtype (PCDS3) shows resistance to therapy and may benefit from targeting the MDK-SDC2 axis with sunitinib.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Therapy resistance is a major challenge in colon adenocarcinoma (COAD).
- Dysregulation of programmed cell death (PCD) pathways impacts therapeutic response and the tumor microenvironment (TME).
- The integrated role of PCD in COAD's TME and clinical heterogeneity is not well understood.
Purpose of the Study:
- To classify COAD subtypes based on PCD pathways.
- To analyze the genomic, TME, and therapeutic features of these subtypes.
- To identify potential therapeutic strategies for resistant COAD.
Main Methods:
- Integrated transcriptomic data from 1,140 COAD patients using non-negative matrix factorization (NMF) to establish Programmed Cell Death-related Subtype (PCDS) classification.
- Validated subtypes in independent cohorts.
- Characterized subtypes using multi-omics data, computational drug repositioning, molecular docking, and in silico drug sensitivity analyses.
Main Results:
- Identified three robust PCDS subtypes: PCDS1 (immune-activated), PCDS2 (WNT/TP53 signaling), and PCDS3 (mesenchymal, T-cell dysfunction/exclusion).
- PCDS3, enriched with iCAFs, showed poor prognosis and resistance to chemotherapy and immunotherapy.
- Discovered MDK-SDC2 axis activation in PCDS3, linked to T-cell dysfunction, and identified sunitinib as a potential drug targeting PCDS3.
Conclusions:
- Defined novel molecular subtypes for COAD based on PCD dysregulation, TME remodeling, and therapeutic outcomes.
- The MDK-SDC2 axis is implicated in stromal-mediated immunotherapy resistance in PCDS3.
- Targeting the MDK-SDC2 axis with sunitinib may overcome resistance in lethal PCDS3 tumors.
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