Collagen 1-mediated CXCL1 secretion in tumor cells activates fibroblasts to promote radioresistance of esophageal cancer

Esophageal squamous-cell carcinoma (ESCC) is commonly treated with radiotherapy; however, radioresist-ance hinders its clinical effectiveness, and the underlying mechanism remains elusive. Here, we develop patient-derived xenografts (PDXs) from 19 patients with ESCC to investigate the mechanisms driving radio -resistance. Using RNA sequencing, cytokine arrays, and single-cell RNA sequencing, we reveal an enrich-ment of cancer-associated fibroblast (CAF)-derived collagen type 1 (Col1) and tumor-cell-derived CXCL1 in non-responsive PDXs. Col1 not only promotes radioresistance by augmenting DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Directly interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo. Collectively, our study provides a comprehensive understanding of the molecular mechanisms under-lying radioresistance and identifies potential targets to improve the efficacy of radiotherapy for ESCC.

Automated summary

This study investigates the mechanisms driving radioresistance in esophageal squamous-cell carcinoma (ESCC) by analyzing patient-derived xenografts (PDXs). The findings reveal the enrichment of collagen type 1 (Col1) derived from cancer-associated fibroblasts (CAF) and CXCL1 derived from tumor cells in non-responsive PDXs. Col1 not only promotes radioresistance by enhancing DNA repair capacity but also induces CXCL1 secretion in tumor cells. Additionally, CXCL1 further activates CAFs via the CXCR2-STAT3 pathway, establishing a positive feedback loop. Interfering with tumor-cell-derived CXCL1 or inhibiting the CXCL1-CXCR2 pathway effectively restores the radiosensitivity of radioresistant xenografts in vivo.