# DDR2-COL11A1 Transcriptional Coupling as a Candidate Therapeutic Target in Colorectal Cancer: Integrative Transcriptomic and Deep Learning Validation

## TL;DR

This study identifies DDR2-COL11A1 transcriptional coupling as a key mechanism in colorectal cancer progression and a potential new therapeutic target.

## Contribution

The paper introduces DDR2-specific transcriptional coupling as a novel mechanism in colorectal cancer, validated through deep learning and transcriptomic analysis.

## Key findings

- DDR2-COL11A1 coupling intensifies significantly from normal to cancerous tissue, with a 2.59-fold increase in correlation.
- Deep learning models achieved 93.14% accuracy in classifying disease stages, with DDR2-COL11A1 identified as the most important gene interaction.
- COL11A1 is upregulated 1.99-fold in cancer, despite stable DDR2 expression, suggesting coupling efficiency as the key mechanism.

## Abstract

Extracellular matrix (ECM) remodeling is a hallmark of colorectal cancer progression, yet the transcriptional mechanisms coordinating collagen deposition and matrix metalloproteinase activation remain incompletely understood. We performed integrated computational analysis of 680 samples across normal mucosa, adenoma, and carcinoma stages to characterize discoidin domain receptor (DDR)-mediated transcriptional networks during tumorigenesis. Stage-stratified correlation analysis of fourteen pathway genes revealed profound divergence between DDR1 and DDR2; DDR1 correlations remained weak across all stages, while DDR2 correlations strengthened 2.59-fold from normal to carcinoma. DDR2-COL11A1 exhibited the most dramatic coupling intensification, increasing from R2=0.007 in normal tissue to R2=0.549 in carcinoma, accompanied by 1.99-fold COL11A1 upregulation. Remarkably, pathway activation occurred despite stable DDR2 expression, indicating enhanced transcriptional coupling efficiency rather than receptor upregulation as the primary mechanism. Deep neural network classification achieved 93.14% accuracy distinguishing disease stages, with SHAP analysis independently validating DDR2-COL11A1 as the most important gene interaction for cancer classification. These findings establish DDR2-specific transcriptional coupling as a functionally important mechanism in colorectal cancer progression and identify COL11A1 as a critical downstream target, suggesting novel therapeutic strategies targeting coupling efficiency rather than receptor abundance.