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

作者：Xinyu Yang, Xinjie Chen, Shaosen Zhang, Wenyi Fan, Ce Zhong, Tianyuan Liu, Guoyu Cheng, LIANG BO ZHU, Qingyi Liu, Yiyi Xi, Wen Tan, Dongxin Lin, Chen Hsuan Wu · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.113270 · 被引用次数：42 · 研究领域：Esophageal Cancer Research and Treatment、Cancer Cells and Metastasis、Immune cells in cancer

Esophageal squamous-cell carcinoma (ESCC) is commonly treated with radiotherapy; however, radioresistance 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 radioresistance. Using RNA sequencing, cytokine arrays, and single-cell RNA sequencing, we reveal an enrichment 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 underlying radioresistance and identifies potential targets to improve the efficacy of radiotherapy for ESCC.